Toronto Lung Transplant Program and Thoracic Surgery Research Laboratory, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
Correspondence: Correspondence and requests for reprints should be addressed to Shaf Keshavjee, M.D., Toronto Lung Transplant Program, Toronto General Hospital, 200 Elizabeth Street, EN 10-224, Toronto, ON, M5G 2C4 Canada.
Ischemia–reperfusion–induced lung injury is characterized
by nonspecific alveolar damage, lung edema, and hypoxemia occurring
within 72 hours after lung transplantation. The most severe
form may lead to primary graft failure and remains a significant
cause of morbidity and mortality after lung transplantation.
Over the past decade, better understanding of the mechanisms
of ischemia–reperfusion injury, improvements in the technique
of lung preservation, and the development of a new preservation
solution specifically for the lung have been associated with
a reduction in the incidence of primary graft failure from approximately
30 to 15% or less. Several strategies have also been introduced
into clinical practice for the prevention and treatment of ischemia–reperfusion–induced
lung injury with various degrees of success. However, only three
randomized, double-blinded, placebo-controlled trials on ischemia–reperfusion–induced
lung injury have been reported in the literature. In the future,
the development of new agents and their application in prospective
clinical trials are to be expected to prevent the occurrence
of this potentially devastating complication and to further
improve the success of lung transplantation.
Key Words: lung transplantation • primary graft failure • acute lung injury • early graft dysfunction • lung preservation
Donor Lung Assessment
Effect of Cold Ischemic Storage
Oxidative Stress
Sodium Pump Inactivation
Intracellular Calcium Overload
Iron Release
Cell Death
Consequences of Ischemia and Reperfusion
Upregulation of Molecules on Cell Surface Membrane
Release of Proinflammatory Mediators
Leukocyte Activation
Strategies to Prevent Lung Dysfunction
Method of Lung Preservation and Reperfusion
Clinical Evidence in Prevention and Treatment of Lung Reperfusion Injury
Future Strategies
Conclusions
Since 1983, lung transplantation has enjoyed increasing success and has become the mainstay of therapy for most end-stage lung diseases. The last decade has been marked by both a significant increase in the number of centers performing lung transplantation and in the number of recipients on the waiting list. The Registry of the International Society for Heart and Lung Transplantation reported in 2002 that almost 15,000 lung transplants have been performed worldwide and that more than 1,500 lung transplants are performed annually (1).
Despite refinements in lung preservation and improvements in surgical techniques and perioperative care, ischemia–reperfusion–induced lung injury remains a significant cause of early morbidity and mortality after lung transplantation. The syndrome typically occurs within the first 72 hours after transplantation and is characterized by nonspecific alveolar damage, lung edema, and hypoxemia. The clinical spectrum can range from mild hypoxemia associated with few infiltrates on chest X-ray to a picture similar to full-blown acute respiratory distress syndrome requiring positive pressure ventilation, pharmacologic therapy, and occasionally extracorporeal membrane oxygenation (2). A number of terms have been used to describe this syndrome, but ischemia–reperfusion injury is most commonly used, with primary graft failure attributed to the most severe form of injury that frequently leads to death or prolonged mechanical ventilation beyond 72 hours . In addition to significant morbidity and mortality in the early postoperative period, severe ischemia–reperfusion injury can also be associated with an increased risk of acute rejection that may lead to graft dysfunction in the long term (3).
| fig.ommitted |
TABLE 1. Terms used to describe ischemia–reperfusion–induced lung injury
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Primary graft failure is the end-result of a series of hits
occurring from the time of brain death to the time of lung reperfusion
after transplantation. Ischemia–reperfusion injury has
been identified as the main cause of primary graft failure.
However, other injuries occurring in the donor before the retrieval
procedure can contribute to and amplify the lesions of ischemia
and reperfusion . Attention of lung transplant physicians
has therefore been focused on selective assessment of donor
lungs, effective technique of lung preservation, and careful
management of transplanted lungs after reperfusion to reduce
the severity of ischemia–reperfusion injury and the incidence
of primary graft failure. Donor lung assessment is an attempt
to select lungs that will be able to handle a period of several
hours of ischemia without significant impairment in their function
after reperfusion. Unfortunately, currently only 10 to 30% of
donor lungs are judged suitable for transplantation (
4).
fig.ommitted
|
Figure 1. Ischemia–reperfusion–induced lung injury may be aggravated by a number of events occurring in the donor before lung retrieval.
| |
Lungs that have been selected for transplantation are generally
flushed with a preservation solution and hypothermically preserved
to decrease their metabolic rate and energy requirement until
implantation in the recipient. The period of cold ischemic storage
is kept as short as possible and usually ranges between 4 and
8 hours according to the location of the donor. Although hypothermia
is essential for organ storage, it is associated with a series
of events such as oxidative stress, sodium pump inactivation,
intracellular calcium overload, iron release, and induction
of cell death that may induce upregulation of molecules on the
cell surface membrane and the release of proinflammatory mediators
that will eventually activate passenger (donor) and recipient
leukocytes after reperfusion. Prolonged ischemia may also result
in a "no-reflow phenomenon" demonstrated by significant microvascular
damages leading to persistent blood flow obstruction and subsequent
ischemia despite reperfusion.
Over the past decade, numerous studies have been performed to optimize the technique of lung preservation. A new preservation solution, which combines a low potassium concentration and dextran, has also been developed specifically for the lungs (5, 6). Several strategies for the prevention and treatment of ischemia–reperfusion–induced lung injury have been introduced into clinical practice and have translated into a reduction in the incidence of severe ischemia–reperfusion injury from approximately 30 to 15% or less (7, 8).
This review will initially focus on donor lung assessment, then the effect of cold ischemic storage with its consequences after reperfusion will be reviewed, and finally the technique of lung preservation and the current strategies for prevention and treatment of ischemia–reperfusion–induced lung injury will be presented.
The success of lung preservation primarily depends on proper
organ selection. Currently, the parameters used to assess donor
lungs are based on donor history, arterial blood gases, chest
X-ray appearance, bronchoscopy findings, and physical examination
of the lung at the time of retrieval (
9). These parameters attempt
to determine function and viability of the lungs, but their
accuracy in determining the risk of reperfusion injury is not
optimal and several centers have extended their donor selection
criteria to the use of nonideal (i.e., extended or marginal)
donors without significant effect on early outcome (
10–
13).
The presence of bilateral infiltrates on chest X-rays, persistent
pus at bronchoscopy, and signs of bronchoaspiration remain,
however, strict contraindications to the use of donor lungs
for transplantation (
14). defines the criteria for
ideal and extended donors as well as
some factors considered
to be strict contraindications to the use of donor lungs for
transplantation. It is recognized, however, that one may chose
to accept increased risk in using lungs for recipients who are
desperately ill.
| fig.ommitted |
TABLE 2. Ideal, extended, and marginal donor selection criteria suggested by the toronto lung transplant group
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The deleterious effect of brain stem death on organ function
has been increasingly recognized over the last few years. Brain
death can induce disruption in homeostatic regulation with profound
disturbances in endocrine function and an intense inflammatory
reaction that may reduce the tolerance of the organs to handle
a period of ischemia (
15–
17). Follette and colleagues
have shown that a bolus of steroids (methylprednisolone approximately
15 mg/kg) administered to all donors after brain death declaration
can improve Pa
O2 and increase lung donor recovery (
18). The
steroid bolus can potentially reduce the inflammatory reaction
and compensate for the deficit in hypophyseal hormones observed
after brain death.
Comparison of organ donation from living and cadaveric donors presents a unique opportunity to study the effect of brain death on clinical outcome. Some authors have shown that kidney biopsies from cadaveric kidney donors had significantly higher levels of inflammatory cytokines, adhesion molecules, and HLA-DR than biopsies from living donors, and the expression of these markers on tubular cells before transplantation was associated with a higher incidence of primary graft dysfunction and early acute rejection (19–21). In human lung transplantation, the chemokine interleukin (IL)-8 has been shown to be upregulated in bronchoalveolar lavage and lung tissue from brain-dead donors, and the level was found to significantly correlate with the incidence of primary graft failure after reperfusion (22, 23). Hence, there is growing body of evidence suggesting that cadaveric donors are exposed to inflammatory events due to brain death, prolonged intubation, episodes of infection and/or hypotension that may increase organ susceptibility to ischemia–reperfusion injury and alloimmune responses. In the future, methods to rapidly assess the degree of inflammation in the lung, for instance by measuring the levels of proinflammatory cytokines and/or adhesion molecules may be extremely useful to determine the type of lung suitable for transplantation and the potential tolerance to prolonged ischemia. These methods would help to reduce the incidence of primary graft failure and to optimize the use of organs available for transplantation.
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EFFECT OF COLD ISCHEMIC STORAGE |
Hypothermia decreases metabolic rate. Therefore, biochemical
reactions are reduced and the rate of degradation of essential
cellular components necessary for organ viability is reduced.
Most enzyme systems show a 1.5- to 2.0-fold decrease in activity
for every 10°C decrease in temperature (
24). However, although
hypothermia is essential during organ storage, a number of events
can still occur leading to activation of inflammatory mediators
that are ultimately deleterious to the preserved organ at the
time of reperfusion.
Oxidative Stress
Oxidative stress is characterized by the formation of reactive oxygen species such as superoxide anion, hydrogen peroxide, and hydroxyl radical (25). These molecules, in particular the hydroxyl radical, are highly unstable and react with the first structure they encounter, usually the lipid component of the cell membrane. Cell injury produced by lipid peroxidation can range from increased permeability to cell lysis. The generation of intracellular oxygen species has been found to be present in most lung parenchymal cells, including endothelial cells, Type II alveolar epithelial cells, Clara cells, and ciliated airway epithelial cells as well as in alveolar macrophages (26). Two important mechanisms lead to the production of reactive oxygen species . One results from the accumulation of hypoxanthine and the conversion of the enzyme xanthine dehydrogenase into xanthine oxidase during anoxia, with the degradation of hypoxanthine into superoxide after reoxygenation (27). The other mechanism depends on the NADPH oxidase system, which is present mainly on the membrane surface of neutrophils and monocytes/macrophages and catalyzes the reduction of oxygen into hydrogen peroxide and superoxide anion (27).
| fig.ommitted |
Figure 2. Formation of reactive oxygen species during ischemia–reperfusion and anoxia–reoxygenation of the lung. The lung has to be considered differently than any other organs because it contains oxygen in the alveoli during the ischemic period. Hence, the oxidative stress resulting from ischemia should be distinguished from the oxidative stress resulting from hypoxia.
| |
Commonly, ischemia–reperfusion corresponds to anoxia–reoxygenation
in organ transplantation. However, the lung has to be considered
differently because it contains oxygen in the alveoli during
ischemic preservation. Alveolar oxygen helps maintains aerobic
metabolism and prevents hypoxia (
28–
30). Hence, in the
lung, the oxidative stress resulting from ischemia should be
distinguished from the oxidative stress resulting from hypoxia.
Hypoxia and, ultimately, anoxia result in a sharp decrease of adenosine triphosphate (ATP) and a corresponding increase in the ATP degradation product hypoxanthine, which generates superoxide when oxygen is reintroduced with reperfusion and/or ventilation. This phenomenon can occur in the lung when alveolar oxygen tension drops below 7 mm Hg during ischemia (31). It can be blocked by inhibitors of xanthine oxidase such as allopurinol (32, 33).
Ischemia is characterized by the absence of blood flow into the lung, which can cause lipid peroxidation and oxidant injury despite the presence of oxygen (29, 32). The mechanism of oxidative stress is different from that occurring during anoxia–reoxygenation because it is not associated with ATP depletion, and it can occur during the storage period (29, 30, 32). In addition, it cannot be blocked by inhibitors of xanthine oxidase (32, 34).
The endothelium appears to be one of the predominant sources of oxidants during nonhypoxic lung ischemia (34). Endothelial cells are highly sensitive to physical forces resulting from blood flow variation and are able to transform these mechanical forces into electrical and biochemical signals (mechanotransduction) (35). The absence of the mechanical component of flow during lung ischemia stimulates membrane depolarization of endothelial cells with the activation of NADPH oxidase, nuclear factor-B, and calcium/calmodulin-dependent nitric oxide synthase (NOS) (34, 36). Other cells such as macrophages and/or marginated neutrophils, which are known to have a high NADPH oxidase activity, could also contribute to the lung oxidant burden that takes place during the ischemic storage (37, 38).
Sodium Pump Inactivation
The sodium (Na+/K+-ATPase) pump is important to preserve proper intracellular electrolyte concentration (high K+, low Na+) and to maintain adequate clearance of alveolar fluid. Hypothermic storage results in the loss of function of the sodium pump, which returns to normal activity with rewarming to 37°C if the epithelial cells are not damaged (39). The loss of function of the sodium pump results in accumulation of sodium in the cell resulting in cell swelling. This is associated with an influx of chloride inside the cell and an efflux of K+ out of the cell. Preservation solutions contain electrolytes and colloid to create an osmotic pressure gradient in an attempt to prevent hypothermia-induced cell swelling. Preservation of organs at 10°C has been proved to be superior than at 4°C, and this has been attributed to better preservation of function of the Na+/K+-ATPase activity (40). The sodium pump activity has also been shown to resume better functional activity at the time of rewarming if the lungs are preserved with extracellular-type preservation solutions that contain low K+ and high Na+ concentrations (41).
Intracellular Calcium Overload
Hypothermic storage alters calcium metabolism in cells both by release of calcium from intracellular depots and by pathologic influx through the plasma membrane (24). The alteration of pH and intracellular calcium concentration disrupt many intracellular processes causing cellular damage (24). Elevated cytosolic calcium can also enhance the conversion of xanthine dehydrogenase to xanthine oxidase and potentiate the damaging effect of free radicals on mitochondria (25).
Support of a role for calcium overload in the mechanism of ischemia–reperfusion injury has been demonstrated by the protective effect of verapamil, a calcium channel blocker, on ischemic injury (42). The effect has been found to be optimal when it is administered to the donor before lung retrieval because it can reduce lipid peroxidation during ischemia and prevent endothelial damage after reperfusion (42, 43). Similar results have been observed with other calcium channel blockers such as nifedipine and diltiazem (44).
Iron Release
Although iron is an essential element for all living cells, it can be highly toxic under pathophysiologic or stress conditions because of its ability to participate in the generation of powerful oxidants. In its free form, iron can cycle between the oxidized (Fe3+) and reduced state (Fe2+), and catalyze the transformation of hydrogen peroxide and superoxide into the highly reactive hydroxyl radical through the Fenton reaction . In addition, free iron facilitates the decomposition of lipid hydroperoxides and accelerates the nonenzymatic oxidation of glutathione. Free iron can be released from ferritin and cytochrome P-450 during ischemia by a number of factors such as acidosis, proteolysis, and superoxide (45–47). In addition to tissue oxidation, iron can be released into the circulation where it can potentially activate platelet aggregation (46, 48).
| fig.ommitted |
Figure 3. Fenton reaction. Iron can cycle between the oxidized and reduced state, and catalyze the transformation of hydrogen peroxide and superoxide into the highly reactive hydroxyl radical.
| |
The importance of iron in promoting ischemia–reperfusion
injury has been demonstrated by the increased injury observed
in iron-supplemented tissue and by the protection offered by
the iron chelator, deferoxamine (
45,
49,
50). Recently, a novel
iron chelator (desferriexochelin 772SM) has been shown to enhance
the effect of a P-selectin antagonist in preventing ischemia–reperfusion
injury in a rat liver model (
51). Lazaroids, which are aminosteroids
inhibiting iron-dependent lipid peroxidation, have also shown
good results in protecting the lung from ischemia–reperfusion
injury in most studies (
52,
53).
Cell Death
Using in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining as a marker of apoptosis, we have observed in human lung transplantation that lungs with excellent function and good clinical outcome have up to 30% of their cells undergoing apoptosis within 2 hours of reperfusion (54). Similar findings have been observed experimentally after 6 and 12 hours of cold ischemic time in rats, whereas longer ischemic times were associated with a preponderance of necrotic cells in lung tissue (55). In contrast to necrosis, apoptosis is not present during ischemia, its presence peaks rapidly after reperfusion and does not correlate with lung function (54–56).
Apoptosis induction is triggered and modulated by two pathways . The intrinsic pathway involves the mitochondria and is activated by reactive oxygen species, whereas the extrinsic pathway is activated by the ligation of death receptors with their ligands—such as tumor necrosis factor (TNF) with TNF-receptors and Fas with Fas-ligand (57). Although the first pathway is activated in the early phase after reperfusion, the second may take up to several hours to induce apoptosis (58).
| fig.ommitted |
Figure 4. After receiving a death signal, cells can undergo either programmed cell death or necrotic cell death. During the course of the most quiescent form of programmed cell death, "classical" apoptosis, caspase 8 and/or caspase 9 are activated through the external pathway (A) or the mitochondrial pathway (B), respectively. Both pathways lead to the activation of caspase 3. Cells, which fail to execute the "classical" apoptotic process, may either be salvaged and return to function, or undergo apoptosis-like or necrosis-like programmed cell death.
| |
Whether apoptotic cells have a deleterious impact on organ function
remains controversial. Some authors have demonstrated that ischemia–reperfusion
injury of kidneys and hearts is reduced when antiapoptotic agents
are injected before reperfusion in mice models of warm ischemia
(
59,
60). However, other investigators have argued that by blocking
the apoptotic molecular cascade after a period of brain ischemia,
injured cells may not be able to recover but may instead continue
to release proinflammatory agents and subsequently die by necrosis,
a mode of cell death more injurious to surrounding tissue (
61).
We have observed that for a similar amount of dead cells in
the transplanted lung, the presence of apoptotic cells was associated
with better lung function than if the cells had died by necrosis
(
62).
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CONSEQUENCES OF ISCHEMIA AND REPERFUSION |
Upregulation of Molecules on Cell Surface MembraneAdhesion molecules. Adhesion molecules can be differentiated
into three major families, the selectins, the immunoglobulin
superfamily, and the integrins. Leukocyte emigration involves
the sequential events of rolling, adherence, activation, and
extravasation. Leukocyte rolling is dependent on selectin-mediated
interaction between endothelial cells (P-selectin and E-selectin)
and leukocytes (L-selectin). Firm adherence and activation of
leukocytes occur when leukocyte ß1-integrin or ß2-integrin
binds to endothelial cells expressing intercellular adhesion
molecule-1 or vascular endothelial adhesion molecule-1, respectively.
Finally, leukocyte extravasation into the tissue is dependent
on integrin-immunoglobulin interactions, involving intercellular
adhesion molecule-1 and platelet endothelial cell adhesion molecule-1.
Adhesion molecules are upregulated on pulmonary endothelial cells during ischemia, and blockade of adhesion molecules such as P-selectin, intercellular adhesion molecule-1, and CD18 (ß-chain of the ß2-integrin) at the time of reperfusion can reduce lung reperfusion injury (63–67). E-selectin and L-selectin blockade may also be beneficial after several hours of reperfusion when neutrophils have a preponderant role (64, 68, 69). The use of biostable analogs of the oligosaccharides Lewis X and Lewis A, which are potent ligands for selectin adhesion molecules, have also been shown to reduce ischemia–reperfusion injury when given before reperfusion (70–72).
Prothrombotic and antifibrinolytic factors.
Hypoxia can induce endothelial cells and macrophages to develop procoagulant properties, which may contribute to the formation of microvascular thrombosis and impede the return of blood flow after reperfusion. In vitro studies have shown that endothelial cells subjected to hypoxia can suppress their production of the anticoagulant cofactor thrombomodulin and increase their production of a membrane-associated factor X activator (73). Tissue factor has also been shown to be upregulated on endothelial cells and macrophages by hypoxia and to play a significant role in modulating ischemia–reperfusion injury in a warm ischemia liver model (74). The administration of C1-esterase inhibitor, which inhibits the classic pathway of the complement system as well as the contact phase and the intrinsic pathway of the coagulation system, has been shown to improve early lung function and to reduce ischemia–reperfusion injury in a dog model of single lung transplantation (75). C1-esterase inhibitor has also been used to treat lung graft failure in two patients, but further clinical studies are required to prove its efficiency (76).
Recent experiments have shown that mice placed in a hypoxic environment suppress their fibrinolytic axis by increasing macrophage release of plasminogen activator inhibitor-1 and decreasing macrophage release of tissue-type plasminogen activator and urokinase-type plasminogen activator (77). Additional studies in mice have shown that the beneficial effect of heme oxygenase-1, carbon monoxide, and IL-10 during lung ischemia is partially mediated by their ability to potentiate the fibrinolytic axis (78, 79). The role of prothrombotic and antifibrinolytic agents is a relatively new area of investigation, and further studies are required to determine more precisely the role of fibrinolytic agents in ischemia–reperfusion injury of the lung.
Release of Proinflammatory Mediators
Cytokines.
Clinical and experimental studies have shown that ischemia–reperfusion of solid organs such as the kidney (80), liver (81), heart (82), and lung (83) induces a rapid release of proinflammatory cytokines . In human lung transplantation, measurable amounts of pro- and antiinflammatory cytokines such as TNF-, IFN-, IL-8, IL-10, IL-12, and IL-18 can be measured in lung tissue during the cold ischemic time and after reperfusion (23). Although most cytokine levels decreased after reperfusion, the chemokine IL-8 significantly increased after reperfusion. Donor parameters including oxygen tension, cause of brain death, smoking history, positive sputum cultures, and time on ventilator did not appear to influence the cytokine levels. However, the age of the donor was inversely correlated with the levels of IL-10 after reperfusion. Because IL-10 is an important antiinflammatory cytokine, this may explain why lungs from older donors might be more susceptible to ischemia–reperfusion injury and are associated with higher postoperative mortality rates (84).
| fig.ommitted |
TABLE 3. Source and function of cytokines potentially involved in reperfusion injury during lung transplantation
| |
A striking relationship between IL-8 levels and graft function
can also be observed after human lung transplantation (
23).
IL-8, which is a potent chemokine-promoting neutrophil migration
and activation, rapidly increased after reperfusion. IL-8 levels
in lung tissue 2 hours after reperfusion negatively correlated
with lung function assessed by the Pa
O2/F
IO2 ratio and the mean
airway pressure, and positively correlated with the Acute Physiology
and Chronic Health Evaluation Score during the first 24 postoperative
hours in the intensive care unit (
23). In addition, we and others
have shown that high levels of IL-8 in donor lung tissue or
bronchoalveolar lavage are associated with an increased risk
of death from primary graft dysfunction after transplantation
(
22,
23). The potential importance of IL-8 has also been demonstrated
in patients with acute respiratory distress syndrome (
85) and
in clinical liver transplantation (
86). In addition, Sekido
and colleagues (
87) have shown that the intravenous administration
of anti–IL-8 antibody at the beginning of the reperfusion
period markedly reduces lung injury and neutrophil infiltration
3 hours after reperfusion in a rabbit model of warm lung ischemia.
The potential mechanism of interaction between leukocyte activation
and cytokine release in ischemia–reperfusion injury during
lung transplantation is shown in .
fig.ommitted
|
Figure 5. The potential mechanism of interaction between leukocyte activation and cytokine release during ischemia and reperfusion of the lung. Ischemia triggers the activation of passenger macrophages, which release proinflammatory cytokines and mediate reperfusion injury during the early phase of reperfusion. IL-8, IL-12, IL-18, TNF-, and IFN- will then activate recipient neutrophils and T-lymphocytes, which will trigger the delayed phase of reperfusion injury and perpetuate lung tissue damage. T-lymphocytes infiltrate lung tissue more rapidly than neutrophils and may also participate in the activation of recipient neutrophils after reperfusion.
| |
Lipids.Cellular injury is accompanied by a rapid remodeling of membrane
lipids with the generation of bioactive lipids that can serve
as both intra- and/or extracellular mediators. Phospholipases
such as phospholipase A
2, phospholipase C, phospholipase D,
and sphingomyelinase play a pivotal role in the generation of
these lipid mediators. Among them, phospholipase A
2 has been
detected in a wide variety of inflammatory conditions such as
ischemia–reperfusion.
The activation of phospholipase A2 induces the production of platelet-activating factor, an extraordinarily potent mediator of inflammation, and mobilizes arachidonic acid from the membrane lipid pool, which will then be degraded by two major pathways into eicosanoids. The potent vaso- and bronchoconstrictor thromboxane A2 as well as various prostaglandins (PGs) such as PGD2, PGE2, PGF2, and PGI2 are produced via the cyclo-oxygenase pathway. The lipoxygenase pathway, on the other hand, catalyzes leukotrienes such as leukotriene-B4, C4, D4, and E4, which can increase capillary permeability.
Phospholipase A2 comprises a constantly growing family of enzymes that have been divided into subgroups based on structural homology and numbered by their order of discovery (88). These enzymes differ in cellular localization and mechanisms of release (88). Recently, Group II secretory phospholipase A2 has been found to play a major role in acute lung injury. Its level has been found to be elevated in bronchoalveolar lavage fluid from humans with acute respiratory distress syndrome (89), and animal studies have shown that this form of phospholipase A2 induces acute lung injury after acid aspiration (90), intracheal injection of lipopolysaccharides (91), and after intestinal ischemia–reperfusion injury (92). In addition, Group II secretory phospholipase A2 has been shown to directly mediate surfactant dysfunction in guinea pigs (91).
To date, only few studies have analyzed the effect of phospholipase A2 inhibitors in lung ischemia–reperfusion injury (93, 94). However, these inhibitors were not specific for Group II secretory phospholipase A2, and they may well have blocked the generation of some PGs such as PGE2 and PGI2. Specific Group II secretory phospholipase A2 inhibitors have been developed recently, and further studies should help elucidate this issue in the future (95).
Platelet-activating factor can be released by a wide variety of cells including macrophages, platelets, endothelial cells, mast cells, and neutrophils. It exerts its biological effects by activating the platelet-activating factor receptors, which consequently activate leukocytes, stimulate platelet aggregation, and induce the release of cytokines and the expression of cell adhesion molecules (96). Platelet-activating factor has been difficult to analyze because it is rapidly degraded by tissue and plasma platelet-activating factor acetylhydrolases. Because there are no specific inhibitors for the biosynthesis of platelet-activating factor, most studies have shown the importance of platelet-activating factor by blocking its receptor.
Platelet-activating factor has been shown to play a critical role in initiating lung injury. The most direct evidence was published recently by Nagase and colleagues who demonstrated that platelet-activating factor receptor knockout mice developed less severe acute lung injury after acid aspiration, whereas the overexpression of platelet-activating factor receptor in transgenic mice exaggerated the injury (97). A number of studies have demonstrated that the administration of antagonists of platelet-activating factor during the ischemic storage and after reperfusion reduce ischemia–reperfusion injury and improve lung function (98–100). Similar results have been observed when platelet-activating factor acetylhydrolase was administered to the flush solution and after reperfusion to increase the degradation rate of the molecule (101).
Arachidonic acid metabolites such as leukotrienes and thromboxanes have been shown to increase in the lung during ischemia–reperfusion injury in a dog model of warm ischemia (102, 103). Thromboxanes may contribute to reperfusion injury and exacerbate lung edema (104). In addition, mast cells, which are known to release large amounts of leukotrienes and histamine, are increased in number after lung ischemia and reperfusion (102). The administration of mast cell membrane-stabilizing agents have also been shown to improve lung function after reperfusion, indirectly demonstrating the importance of leukotrienes (105, 106).
Complement.
Studies in ischemia–reperfusion injury of the lung have shown that activation of the complement system after reperfusion may lead to cellular injury through direct and indirect mechanisms (107, 108). Products of complement activation cause smooth muscle contraction and increased vascular permeability and induce degranulation of phagocytic cells, mast cells, and basophils (109). The activated complement fragment C5a is also capable of amplifying the inflammatory response via its chemoattractant properties, its induction of granule secretion in phagocytes, and its ability to induce neutrophil and monocyte/macrophage generation of toxic oxygen metabolites (110). Activation of complement fragments C3 and C5 is also essential for the activation of the complement cascade and the generation of the membrane attack complex, which leads to direct cell lysis (111).
Complement receptor-1 is a natural complement antagonist that has been cloned and the transmembrane portion removed to obtain a soluble form of complement receptor-1. This soluble form suppresses complement activation in vivo by inhibiting C3 and C5 convertases, which prevent the activation of both the classic and alternative pathways. In a swine single lung transplant model, we and others have shown that the administration of soluble complement receptor-1 to the recipient before reperfusion reduced lung edema, decreased neutrophil accumulation, and improved oxygenation of the transplanted lung (112, 113). Recently, Stammberger and colleagues have demonstrated in a rat lung transplant model that the administration of a molecule combining soluble complement receptor-1 with sialyl Lewis X, a selectin receptor antagonist, can achieve even better results than the administration of soluble complement receptor-1 alone (72). This study highlights the fact that several pathways may need to be blocked to address the redundancy of the inflammatory system.
Endothelin.
Endothelins are powerful vasoconstrictors—10 times more active than angiotensin II or vasopressin (114). Three isoforms have been described in human and other mammals, endothelin-1, endothelin-2, and endothelin-3, of which endothelin-1 has been most extensively studied because it is released by endothelial cells and smooth muscle cells and its expression is predominant in the lung (114). In addition to being a potent vasoconstrictor, endothelin-1 can stimulate the production of cytokines by monocytes/macrophages and promote the retention of neutrophils in the lung (115).
Clinical and experimental studies in lung transplantation have shown that endothelin-1 can accumulate in lung tissue before and during the first few hours after reperfusion (116, 117). High levels of endothelin-1 can then lead to an increased expression of vascular endothelial growth factor and increase vascular permeability (118). The role of endothelin-1 in ischemia–reperfusion injury has been demonstrated by the improvement in lung function when endothelin receptor antagonists are administered before or during reperfusion (100, 119, 120). The administration of endothelin-1 receptor antagonist was associated with a reduction in the expression of inducible NOS and a lower proportion of apoptotic cells in the lung after reperfusion (121).
Leukocyte Activation
Experimental and clinical evidence suggest that ischemia–reperfusion injury occurs in a biphasic pattern. The early phase of reperfusion, which depends primarily on donor characteristics, and the delayed phase of reperfusion, which occurs over the ensuing 24 hours and depends primarily on recipient factors (122). Donor/passenger macrophages are activated during ischemia and mediate the early phase of reperfusion injury, whereas recipient lymphocytes and neutrophils are primarily involved in the delayed phase of reperfusion injury (123–126). The recruitment of lymphocytes and neutrophils into the lung results from the release of cytokines and other mediators before and after reperfusion (23). The potential mechanism of interaction between the cytokine release and the activation of macrophages, lymphocytes, and neutrophils during ischemia–reperfusion injury in lung transplantation is shown in .
Macrophages.
Alveolar macrophages can produce a large number of cytokines and procoagulant agents in vitro in response to oxidative stress (74, 127). In an in vivo model of warm ischemia, Eppinger and colleagues demonstrated the importance of TNF-, IFN-, and macrophage chemoattractant protein-1 in the early phase of reperfusion and suggested that alveolar macrophages could have an important role immediately after reperfusion (126). Fiser and colleagues recently confirmed this hypothesis by specifically inhibiting pulmonary passenger macrophages with gadolinium chloride injected into the donor before a period of cold ischemia (125). They showed that lungs, in which passenger macrophages were inhibited, had significantly better function immediately after reperfusion and this was independent of neutrophil inhibition.
Lymphocytes.
Evidence suggests that lymphocytes may have an important role in ischemia–reperfusion injury. Richter and colleagues demonstrated that human lung donor parenchyma contains a large number of passenger macrophages and activated lymphocytes, among which T cells and natural killer cells predominate (128). Similar findings have been observed in liver transplantation with a large number of activated CD8+ T cells, T cells, and natural killer cells being transmitted with the liver graft to the recipient (129–132). Although the role of these passenger lymphocytes has not been extensively explored in the setting of ischemia–reperfusion injury, recent studies have demonstrated that nude mice, CD4+/CD8+ knockout mice, and CD4+ depleted mice have significantly less severe reperfusion injury of the liver and kidney than control mice (123, 133, 134). In addition, Clavien and colleagues have shown in an ex vivo model of liver reperfusion that cold preservation induces an increase in lymphocyte adherence within the first 10 minutes of reperfusion and that these infiltrating lymphocytes could be important in mediating graft dysfunction (135). We have recently demonstrated by flow cytometry in a rat lung transplant model that recipient CD4+ T cells rapidly accumulate in lung tissue after reperfusion. CD4+ T cells then upregulate CD25, a potential marker of activation, and participate in ischemia–reperfusion injury in the delayed phase of reperfusion by releasing IFN- (136).
Neutrophils.
Neutrophils progressively infiltrate the transplanted lung during the initial 24 hours of reperfusion (137). Although they certainly play an important role in perpetuating reperfusion injury, their function in the early phase of reperfusion is less predominant. Using an isolated rat lung perfusion model, Deeb and colleagues demonstrated that the addition of neutrophils to the perfusion system was not necessary for the induction of reperfusion injury after a period of warm ischemia (138). Following this line of experimentation, the same group demonstrated that reperfusion injury exhibits a bimodal pattern, consisting of neutrophil-independent events during the first few hours of reperfusion and of neutrophil-mediated events after 4 hours of reperfusion (124). Further studies with specific antibodies against neutrophils have confirmed these findings and show that other leukocytes such as macrophages have a more important role in the early phase of reperfusion (125, 139, 140).
| |
STRATEGIES TO PREVENT LUNG DYSFUNCTION |
Method of Lung Preservation and ReperfusionLung preservation solution.Currently, the vast majority of centers have adopted a single
pulmonary artery flush to preserve the lungs because of its
technical simplicity (
141). Preservation solutions that have
been studied include mainly intracellular-type solutions (high
K
+, low Na
+ solutions) such as Euro-Collins and University of
Wisconsin solution, and extracellular-type solutions (low K
+,
high Na
+ solutions) such as low-potassium dextran (LPD) and
Celsior . Historically, Euro-Collins was developed
for kidney preservation, University of Wisconsin for liver preservation,
and Celsior for heart preservation. LPD is the only solution
that has been specifically developed for lung preservation.
LPD-glucose solution (Perfadex; Vitrolife, Goteborg, Sweden)
has been approved for clinical practice, and many centers have
switched to the use of LPD-glucose as their clinical lung preservation
solution.
| fig.ommitted |
TABLE 4. Composition of preservation solutions
| |
The concept of using a modified extracellular fluid solution
to preserve the lung was developed in Japan in the mid-1980s.
Fujimura and colleagues demonstrated that a modified extracellular
solution was superior to the intracellularly based Euro-Collins
solution for prolonged lung allograft preservation (
5). After
these experiments, Keshavjee and colleagues demonstrated that
the association of low-potassium (4 mmol/L) and dextran 40 reliably
and reproducibly provided significantly better lung function
than Euro-Collins after 12 hours of ischemic time in a canine
single lung transplantation model (
6). The same group further
demonstrated that both dextran 40 and the low-potassium concentration
were critical components of the LPD solution (
142,
143). After
these experiments, Date and colleagues observed that the addition
of 1% of glucose to the LPD solution provided a substrate for
the aerobic metabolism that takes place in the inflated lungs
and allowed safe extension of the ischemic time to 24 hours
in dogs (
28). Steen and colleagues, as well as other groups,
repeated these experiments and found safe pulmonary preservation
for 12 to 24 hours with LPD-glucose in porcine, canine, and
primate models of left single and double lung transplantation
(
144–
147).
Ultrastructural analyses have shown significantly better conservation of lung integrity with extracellular-type preservation solutions than with intracellular-based solutions (148). Better ultrastructural appearance may not translate into better lung function after short ischemic periods, but after prolonged ischemic time, i.e., 8 hours or longer, lungs preserved with LPD solution have always shown better lung function than lungs preserved with intracellular-type preservation solutions (149–151).
Celsior, which is an extracellular-type preservation solution specifically developed for the heart, has also been shown to achieve satisfactory results in lung preservation (152–155). Some authors have suggested that Celsior might even be better than LPD in lung preservation (156, 157). Celsior, in contrast to LPD, contains high amounts of reduced glutathione, histidine, and lactobionate, which may play an important role in the prevention of free radical injury (158). Future studies should determine if the addition of antioxidants and/or radical scavengers could further enhance the quality of preservation with LPD solution.
As previously mentioned, the beneficial effect of preservation with LPD is due to the combination of both a low potassium concentration and the presence of dextran (142). The low potassium concentration may be less detrimental to the functional and structural integrity of endothelial cells, which may thus lead to less production of oxidants (34, 37, 38) and release of less pulmonary vasoconstrictors (143, 159–161). Dextran 40 is a macromolecule with an average molecular weight of 40,000 D exerting an oncotic pressure of 24 mm Hg when diluted at a concentration of 5% (162). Dextran improves erythrocyte deformability, prevents erythrocyte aggregation, and induces disaggregation of already aggregated cells, in addition to an antithrombotic effect induced by coating endothelial surfaces and platelets (142). These effects improve pulmonary microcirculation and preserve the endothelial–epithelial barrier, which may secondarily prevent the no-reflow phenomenon and reduce the degree of water and protein extravasation at the time of reperfusion (163). In addition, in vitro studies have demonstrated that LPD solution can (1) exert a suppressive effect on polymorphonuclear chemotaxis (164), (2) be less cytotoxic for Type II pneumocytes (165, 166), and (3) maintain better activity of alveolar epithelial Na+/K+-ATPase function during the cold ischemic period when compared with Euro-Collins or University of Wisconsin solutions (167). These effects may result in less lipid peroxidation, and better surfactant function at the end of the ischemic time and after reperfusion (168, 169).
Raffinose is a trisaccharide sugar with a mean molecular weight of 594 D that prevents pulmonary water diffusion and cellular swelling in a more efficient way than do monosaccharides and dissaccharides (170). Raffinose has been demonstrated to be one of the essential components of the University of Wisconsin solution when compared with Euro-Collins solution in an ex vivo rat model of lung graft reperfusion (171). The addition of raffinose (30 mmol/L) to LPD-glucose has been shown to reduce the peak airway pressures and to improve oxygenation of the transplanted lung after 24 hours of ischemic time in a rat single lung transplant model (172). The addition of raffinose to the LPD-glucose solution can result in less tissue damage and better cellular integrity at the end of the ischemic time (173).
Clinical reports from three centers have compared the effect of LPD-glucose (Perfadex; Vitrolife, Uppsala, Sweden) with an historical control group of lungs preserved with Euro-Collins (174–176). All three reports showed significantly better lung function on arrival in the intensive care unit and a trend toward lower 30-day mortality with LPD-glucose . An additional report demonstrated that, after adjustment for graft ischemic time, extracellular-type preservation solutions were associated with a decreased incidence of primary graft failure after lung transplantation when compared with intracellular-type preservation solutions (153). Currently, the limitation in extending the ischemic time is more often related to the increasing use of nonideal lung donors rather than to poor lung preservation (14). In our experience, the ischemic time with LPD preservation has been successfully extended up to 12 hours with excellent donors.
| fig.ommitted |
TABLE 5. Comparisons of low-potassium dextran glucose and euro-collins in clinical lung transplantation
| |
In conclusion, clinical and experimental evidence suggests that
LPD-glucose is currently the preservation solution of choice
for lung transplantation. Continuous refinement is nevertheless
still required, and in the future raffinose as well as other
components such as reduced glutathione, histidine, and/or lactobionate
may be added to the base solution to enhance the quality of
preservation.
Volume, pressure, and temperature of flush solution.
Several studies have analyzed the effect of pressure, volume, and temperature of the preservation solution during flushing. In 1986, after observing that flush-perfusion at low flow rates (3–5 ml/kg/min) achieved poor results after moderate- to long-term storage, Haverich and colleagues performed a study where they compared a low perfusate volume given at a low flow rate (20 ml/kg given in 6 min) with a low perfusate volume given at a high flow rate (20 ml/kg given in 1.3 min) and a high perfusate volume given at a high flow rate (60 ml/kg given in 4 min) (177). They found that lungs flushed with a high perfusate volume given at a high flow rate resulted in significantly better cooling of the lungs and better lung function after reperfusion. This study has never been repeated with additional groups below and/or above 60 ml/kg. However, Steen and colleagues have suggested the use of 150 to 180 ml/kg of LPD-glucose to obtain a more uniform and clean washout of the anterior part of the lungs, which is usually less uniformly flushed because of the pressure gradient in the supine position (144, 145).
More recently, Sasaki and colleagues systematically analyzed the influence of the pulmonary artery pressure during the flushing period on lung preservation (178). They observed that flushing pressures of 10 to 15 mm Hg were associated with complete flushing of the pulmonary vascular beds and achieved significantly better lung function after reperfusion than flushing pressures of 5, 20, and 25 mm Hg in an ex vivo rabbit lung reperfusion model. They also observed that flushing pressures of 20 mm Hg or higher were associated with significantly less endogenous nitric oxide (NO) production, which may have had a detrimental effect on the lungs after reperfusion (179).
The temperature of the flush solution has been the subject of some discussion. Andrade and colleagues have observed in an isolated rat model that hypothermic pulmonary arterial flushing with 60 ml/kg of Euro-Collins solution at a pressure of 15 mm Hg can transiently increase the capillary filtration coefficient and induce persistent lung damage with increased wet to dry weight ratio and biochemical surfactant changes (180). This finding could be explained by two mechanisms, one being the absence of an oncotic component in the Euro-Collins solution to maintain adequate fluid balance between the intravascular and extravascular compartments and the second being the effect of hypothermia on endothelial cells. The use of a cold flushing solution may induce injuries to the alveolocapillary membrane, which could potentially enhance the abnormal relaxation of the vascular endothelium after several hours of ischemia (181, 182).
Wang and colleagues showed that a temperature of 23°C for the flush solution was associated with a lower pulmonary vascular resistance during flushing and more uniform washout of the pulmonary vascular beds than a temperature of 10°C (183). In addition, several authors have observed that lung function was significantly better after reperfusion if the lungs were initially flushed with a temperature of 15 to 20°C instead of 10°C or lower (183–186). However, all these studies were performed in small animals and surface cooling of the inflated lungs was probably more rapid than with larger lungs, thus limiting the period of warm ischemia until core cooling of the lungs was achieved. Steen and colleagues have recommended that if the temperature of the flush solution is kept at room temperature, then the lungs should be maintained in a collapsed state during cold storage to reduce the core temperature quicker by avoiding the insulating effect of air (145).
Ultrastructural analysis of the lungs at various time points during the preservation period shows that the injuries induced by the flush itself appear to be minimal when compared with the insult induced by ischemia on the endothelial–epithelial barrier (187, 188). Hence, despite some potential injuries induced by cold flushing, it appears that this contribution to the total injury is minimal when compared with the insult induced by ischemia. Flushing the lungs with a hypothermic preservation solution should therefore still be recommended.
Inflation, oxygenation, and storage temperature.
Although atelectatic lungs can be preserved at cold temperature for 5 to 6 hours in humans and for up to 24 hours in pigs (189, 190), there have been a large number of experiments since the early 1970s suggesting that preservation of the lung is improved when they are inflated with oxygen (191). Expansion of the lungs with oxygen during the ischemic period protects the lung from injury by three mechanisms: (1) it maintains some aerobic metabolism, (2) it preserves the integrity of pulmonary surfactant, and (3) it preserves epithelial fluid transport.
During ischemia, lungs inflated with air are still able to consume oxygen and to produce energy through the more efficient aerobic metabolic pathway, which prevents the accumulation of cellular metabolites and delay cell death (192, 193). Hence, alveolocapillary membranes are better preserved and the amount of total protein and lactate dehydrogenase in the bronchoalveolar lavage fluid are significantly lower than if the lungs were preserved in a complete atelectatic state or inflated with 100% nitrogen (193, 194). As well, static pulmonary compliance and surfactant secretion remain significantly better if the lungs are preserved in an inflated instead of a deflated state (193–195). In addition, Sakuma and colleagues have recently demonstrated that lung deflation decreases alveolar fluid clearance, whereas fluid clearance was maintained in inflated lungs, independently of the presence of oxygen (196).
Atelectasis is also associated with higher pulmonary vascular resistance and poorer distribution of the lung preservation solution (197, 198). Hence, a recruitment maneuver before flushing the lungs is certainly an effective measure. However, overdistension of the lung by either static inflation, high VT, or high positive end-expiratory pressure has been shown to be detrimental during mechanical ventilation, and there is evidence suggesting that hyperinflation during storage increases the pulmonary capillary filtration coefficient (199–201). In rat experiments, we and others have observed that lung inflation during storage should be limited to 50% of the total lung capacity or to an airway pressure of 10 to 15 cm H2O to avoid barotrauma (195, 202). In our clinical practice, we perform a recruitment maneuver to fully re-expand the lung before flushing them, and we ventilate the lungs with a VT of 10 ml/kg and a positive end-expiratory pressure of 5 cm H2O during the flushing period. The lungs are then inflated with a sustained peak airway pressure of a maximum of 15 to 20 cm H2O before tracheal crossclamping in an effort to obtain complete lung expansion but avoid overdistension. It should be noted that overinflated lungs may be exposed to significantly more overdistension if they are transported in airplanes because of the potentially lower atmospheric pressure during the flight.
Oxygen is required during storage to support aerobic metabolism (192, 202, 203). However, an FIO2 greater than 50% may be associated with more lipid peroxidation during lung storage (29, 192, 202, 204). Hence, inflation with an oxygen fraction of 50% or less is usually recommended in clinical practice.
Several experimental studies have shown that lung preservation at 10°C achieved better results than preservation at 4 or 15°C and higher (40, 202, 205, 206). However, these findings were not confirmed by other groups (207, 208). In addition, lungs preserved at 10°C require a greater amount of metabolic substrate, and the risk of lung injury can increase extremely rapidly if the temperature rises above 10°C during preservation (204). Hence, if a 10°C preservation temperature were used, the temperature of the organs would have to be constantly monitored because of the narrow margin of safety. For this reason, we recommend preservation of the lungs at a temperature ranging between 4 and 8°C .
| fig.ommitted |
TABLE 6. Current recommendations for lung preservation from the toronto lung transplant group
| |
Retrograde flush and late reflush.Retrograde flush, which refers to the administration of the
flush solution through the left atrial appendage or the pulmonary
veins, and drainage through the pulmonary artery, has been described
for lung and heart–lung transplantation (
209,
210). The
technique adds the potential advantages of flushing both the
bronchial and pulmonary vessels and of limiting the effect of
pulmonary arterial vasoconstriction on the distribution of the
flush solution. Experimentally, a retrograde flush has been
found to improve lung preservation when compared with an anterograde
flush. This effect was attributed to more effective clearance
of red blood cells within the capillaries, better distribution
of the flush solution along the tracheobronchial tree, and less
severe impairment of surfactant function (
157,
197,
211,
212).
However, despite the retrograde flush, pretreatment with PGE
1 was still helpful in improving pulmonary dynamic compliance
after reperfusion (
213). After these results, several groups
have adopted a combined procedure with an anterograde flush
through the pulmonary artery followed by a retrograde flush
through each of the pulmonary veins
in situ while the lungs
are still ventilated (
214,
215).
Late reflush was initially described in kidney transplantation and refers to the administration of a second flush immediately before implantation of the graft (216). This method has been shown to wash out inflammatory agents and to improve post-transplant graft function by limiting cell damage after reperfusion (116, 216–218). The University of North Carolina has developed a specific extracellular solution for late reflush (Carolina rinse solution) to replenish important substrates and provide antioxidants and vasodilators to the graft before reperfusion to limit cell injury (219). This solution has been shown to be superior to Euro-Collins for late reflush in an ex vivo model of lung reperfusion (218). In clinical lung transplantation, Venuta and colleagues have completed a study with 14 patients demonstrating that the addition of a late retrograde reflush with LPD-glucose to an anterograde flush was associated with improved lung function when compared with an anterograde flush only (215). Future studies are required to determine whether the improvement in lung function that they observed was due to the retrograde flush and/or to the late reflush effect.
Low reperfusion pressure and protective ventilation.
The pulmonary artery pressure during the initial 10 minutes of reperfusion is of prime importance. Indeed, the endothelial permeability is transiently elevated during this early phase of reperfusion, and irreversible lung damage, pulmonary edema, and leukocyte sequestration can occur if the lung is rapidly reperfused after a period of ischemia (220–222). Progressive reintroduction of blood flow over a 10-minute period has been shown to reduce lung injury and to improve function of the transplanted lung (220, 222, 223). A specially designed pulmonary artery clamp with a larger number of ratchets can be used to gradually increase blood flow during reperfusion of the lung over a 10-minute period. When a transplant is done on cardiopulmonary bypass, the rate of reperfusion can be controlled with the pump.
Although mechanical ventilation is essential for patients undergoing lung transplantation, a number of animal and clinical studies have shown that mechanical ventilation can worsen pre-existing lung injury and produce ventilator-induced lung injury (199). The effect of different modes of ventilation in the early period after lung transplantation has not been explored clinically. However, we have recently demonstrated in a rat single lung transplant model that injurious ventilation with high VT and low positive end-expiratory pressure significantly worsened lung function after 3 hours of reperfusion when compared with a protective mode of ventilation (224). In our practice, we have incorporated a protective ventilation strategy during the initial period of reperfusion. The newly implanted lung allograft is gently reinflated with a sustained airway pressure of 20 cm H2O before reperfusion and then ventilated with an FIO2 of 50%, positive end-expiratory pressure of 5 cm H2O, and pressure-control ventilation limiting the peak airway pressures to 20 to 25 cm H2O (225, 226).
Clinical Evidence in Prevention and Treatment of Lung Reperfusion Injury
Clinical studies in the prevention and treatment of reperfusion injury during lung transplantation are limited. Only three randomized, double-blinded, placebo-controlled trials have been reported in the literature . Most publications are limited to personal experience and case series.
| fig.ommitted |
TABLE 7. Randomized, double-blinded, placebo-controlled clinical trials for ischemia–reperfusion injury in human lung transplantation
| |
Nitric oxide.NO is a messenger gas molecule with many physiologic effects,
including potent vasoregulatory and immunomodulatory properties
(
227). It is produced by a family of enzymes, i.e., NOSs that
catalyzes the conversion of
L-arginine to
L-citrulline with
the help of five cofactors. NO then stimulates soluble guanylyl
cyclase, which catalyzes the formation of cyclic 3'-5'-guanosine
monophosphate, which in turn regulates protein phosphorylation,
ion channel conductivity, and phosphodiesterase activity.
At least two isoforms of NOSs are constitutively expressed. One is restricted to the endothelium (endothelial NOS or NOS-III), whereas the other predominates in neuronal tissue (neuronal NOS or NOS-I). An inducible form of NOSs is found in a wide variety of cell types, such as macrophages, epithelial, and endothelial cells (inducible NOS or NOS-II). Endothelial NOS and neuronal NOS are responsible for many of the beneficial properties of NO such as reduced vascular tone and prevention of neutrophil and/or platelet adhesion, whereas inducible NOS can be induced by a number of stimuli and has been implicated in the killing of exogenous organisms as well as in the pathophysiology of vascular collapse with septic shock, impaired hypoxic vasoconstriction, and tissue injury (228).
Endogenous NO has been found to be decreased after ischemia and reperfusion of the lung in human and animal studies (229–231). This finding may be associated with an increased expression of the enzyme endothelial NOS, which may suggest that endogenously produced NO may be rapidly destroyed by oxygen-free radicals after reperfusion and/or that ischemia–reperfusion may induce the release of endothelial NOS inhibitors in the lung (228, 229).
Multiple strategies have been developed to compensate for the fall in endogenous NO during lung transplantation. These strategies have been applied to the donor and/or to the recipient and have targeted each step of the pathway described previously, including the administration of the upstream precursor molecule L-arginine (232, 233), methods to increase the downstream effector molecule cyclic 3'-5'-guanosine monophosphate (229, 234), and the administration of exogenous NO. Exogenous NO has been given directly by inhalation (inhaled NO) (235–238) or indirectly by infusion of a NO donor, such as FK409 (239, 240), nitroprusside (241–243), glyceryl trinitrate (244), nitroglycerin (245–247), or SIN-1 (248). Other strategies have been directed at increasing the activity of the enzyme NOS by the addition of one of its cofactors (tetrahydrobiopterin) to the preservation solution (249) or by transfecting the donor with an adenovirus containing endothelial NOS before lung retrieval (250).
These strategies have been shown to be effective experimentally and to have a prolonged effect if they are initiated before the onset of reperfusion injury (236–238, 251). However, NO can react with superoxide anion and form peroxynitrous acid, which is a highly reactive oxidant that can induce the release of endothelin-1, damage alveolar Type II cells even after a short period of ischemic time, and cause structural and functional alteration of surfactant (252). Hence, this reaction may explain why some authors have shown that NO administered during ischemia and/or early reperfusion may be ineffective or even harmful, in particular when it is given with a high FIO2 immediately after reperfusion (235, 253–256).
Inhaled NO has been useful clinically to treat ischemia–reperfusion injury of the lung because it can improve ventilation–perfusion mismatch and decrease pulmonary artery pressures without affecting systemic pressures (257–261). However, the role of inhaled NO in preventing ischemia–reperfusion injury during clinical lung transplantation remains controversial. Ardehali and colleagues have shown that the application of inhaled NO to 28 consecutive recipients after lung transplantation did not prevent the occurrence of primary graft failure (262). However, Thabut and colleagues reported that the administration of inhaled NO in combination with pentoxifylline at the time of reperfusion in 23 patients reduced the incidence of ischemia–reperfusion injury when compared with two historical control groups (263). Our group has recently completed a randomized, double-blinded, placebo-controlled trial of inhaled NO administered to lung transplant recipients, starting 10 minutes after reperfusion for a minimum of 6 hours (264). Among a total of 84 recipients, we observed no significant differences in the immediate oxygenation, time to extubation, length of stay in the intensive care unit, or 30-day mortality . In conclusion, although inhaled NO therapy can be useful in improving gas exchange in cases of established reperfusion injury, the role for NO in the prevention of ischemia–reperfusion injury has yet to be demonstrated in clinical lung transplantation.
Prostaglandins.
PGE1 has been shown to be beneficial when added to intracellular preservation solutions such as Euro-Collins and University of Wisconsin (184, 207, 265). The beneficial effect of PGE1 is attributed to its vasodilator properties that may lead to better distribution of the preservation solution and to the stimulation of cyclic-3',5'adenosine monophosphate–dependent protein kinase during the cold ischemic time, which may reduce endothelial permeability, neutrophil adhesion, and platelet aggregation on reperfusion (265).
The continuous intravenous administration of PGE1 to the recipient during the early phase of reperfusion has been shown to reduce ischemia–reperfusion injury of the lung in animal models of lung transplantation (266, 267). Although this effect can be partially attributed to the vasodilator property of PGE1 during the initial 10 minutes of reperfusion (268), after a longer period of reperfusion a continuous PGE1 infusion achieved significantly better lung function than other vasodilator agents such as prostacyclin and nitroprusside (269). Hence, the continuous infusion of PGE1 clearly has a beneficial role on ischemia–reperfusion injury, some of which can be attributable to its antiinflammatory effects. Indeed, the continuous administration of PGE1 during reperfusion is associated with a shift from a proinflammatory cytokine profile including TNF-, IFN-, and IL-12 to an antiinflammatory cytokine profile with increased IL-10 in a rat lung transplant model (266). Other effects of PGE1, such as its antiaggregant action on platelets, may also potentially explain its beneficial role (270, 271).
On the basis of experimental evidence, some centers routinely use an infusion of PGE1 during the postoperative period after lung transplantation, whereas others reserve PGE1 infusion for the treatment of severe reperfusion injury (272). Prospective randomized trials are required to determine whether routine PGE1 has an overall beneficial effect in the postoperative course during clinical lung transplantation. Such studies may use the newly developed aerosolized form of PGE1, which has been shown experimentally to reduce ischemia–reperfusion injury of the lung without having the systemic hypotensive side effect of intravenous PGE1 (243).
Complement inhibition.
After the successful experimental application of the complement inhibitor, soluble complement receptor-1 (112), we performed a multicenter randomized, double-blinded, placebo-controlled trial that included 59 lung transplant recipients (273, 274). Among 29 patients receiving a dose of soluble complement receptor-1 before reperfusion, 14 (48%) were extubated within 24 hours, which was significantly better than in the control arm with only 6 patients extubated out of a total of 30 (20%). In addition, the overall duration of mechanical ventilation and length of intensive care unit stay tended to be shorter in the group receiving the therapeutic drug . The effect of soluble complement receptor-1 appeared to be stronger in the group of patients who underwent cardiopulmonary bypass, but the results did not reach statistical significance because of the small number of patients (n = 12). This likely reflects the added potential benefit of inhibiting complement activation related to cardiopulmonary bypass. The results of Phase III trials in cardiac surgery should confirm whether complement inhibition with the soluble complement receptor-1 is protective when patients are placed on cardiopulmonary bypass circuits (275).
Cardiopulmonary bypass is known to activate the release of mediators and to stimulate the activation of complement factors. We therefore limit the use of cardiopulmonary bypass to recipients with pulmonary hypertension and to those who cannot tolerate unilateral ventilation or perfusion (276). Some centers, however, routinely perform lung transplantation using cardiopulmonary bypass with good results (277). One potentially beneficial effect of cardiopulmonary bypass is the ability to reperfuse the newly implanted lungs with controlled pulmonary artery pressures over a prolonged period of time.
Antagonist of platelet-activating factor.
Wittwer and colleagues have recently reported their clinical experience with an antagonist of platelet-activating factor (BN52021, Ginkolide B) in 24 patients randomly assigned to a high dose of antagonist in the flush solution and after reperfusion (n = 8), a low dose of antagonist in the flush solution and after reperfusion (n = 8), and a control group (n = 8) (278). They observed a trend toward a better alveolar-arterial oxygen gradient within the first 32 hours after reperfusion and better chest X-ray score in the two groups receiving the antagonist (Table 7). In clinical kidney transplantation, a randomized, double-blinded, single center trial with 29 recipients showed a significant reduction in the incidence of primary graft failure after transplantation in the group of patients receiving the antagonist of the platelet-activating factor (279). These promising results from single centers should encourage large multicenter trials.
Surfactant therapy.
Pulmonary surfactant consists of approximately 90% lipids, mainly saturated phosphatidylcholine, and approximately 10% proteins, including the surfactant apoproteins-A, B, C, and D. Type II pneumocytes synthesize, store, secrete, and to a large extent recycle pulmonary surfactants (280). The surfactant pool can be separated into the intracellular surfactant, represented by the lamellar bodies of Type II pneumocytes, and the intra-alveolar surfactant, which consists of several subtypes, including freshly secreted lamellar body-like forms, tubular myelin, the alveolar lining layer, and small unilamellar vesicles. Bronchoalveolar lavage studies usually refer to two subfractions of the intra-alveolar surfactant, large aggregates or heavy forms, largely corresponding to tubular myelin,which are highly active in decreasing the alveolar surface tension, and small aggregates or light forms, largely corresponding to degraded and inactive small unilamellar vesicles (281).
Surfactant dysfunction has been shown to occur during ischemia–reperfusion injury of the lung (281, 282). Ultrastructural analyses have shown an increase in the small to large surfactant aggregate ratio, an increase in sphingomyelin, and a decrease in phosphatidylglycerol and phosphatidylcholine, which correlated with decreased pulmonary compliance and lung oxygenation (281, 283, 284). These changes were also associated with a deficit in surfactant adsorption and a decrease in surfactant apoprotein-A (284–286). Alveolar surfactant dysfunction may occur despite the absence of plasma protein leakage or changes in lamellar bodies of Type II pneumocytes (281, 287). The dysfunction is most likely the result of numerous insults occurring during lung storage such as the production of phospholipase A2, mechanical distorsion, altered phospholipid metabolism, reduced production of surfactant apoprotein-A, and/or accumulation of C-reactive protein (284, 285, 288). Although some alterations in surfactant can be observed immediately after pulmonary artery flushing, most of the alterations have been shown to progressively increase during ischemic storage and to be significantly less with extracelullar-type preservation solutions (282, 283, 286, 288).
Experimental studies and clinical observations have found that exogenous surfactant therapy can improve pulmonary function after lung transplantation (289–294). The administration of exogenous surfactant is associated with a higher amount of total surfactant phospholipid, a higher percentage of the heavy subtype of surfactant, a normalized percentage of phosphatidylcholine, and a higher amount of endogenous surfactant apoprotein-A, which has been shown to improve oxygenation and compliance of the transplanted lung (291, 292). Exogenous surfactant has also been shown to enhance immediate recovery from transplantation injury and to be persistently beneficial for endogenous surfactant metabolism up to one week after transplantation (295). Exogenous surfactant given to the donor before retrieval has been associated with better and more reliable results than when it was administered just before or immediately after reperfusion (290, 291, 293, 296). Struber and coworkers have successfully used a nebulized synthetic surfactant in several patients with reperfusion injury after lung transplantation (294). They observed rapid improvement in pulmonary compliance and in alveolar-arterial oxygen gradient, leading to extubation within a few days after the application (294). In the future, these promising results need to be confirmed by a prospective, randomized trial.
Future Strategies
Heme oxygenase pathway.
Heme oxygenases catalyze the conversion of heme into biliverdin, carbon monoxide, and free iron. The free iron is then sequestred into ferritin, whereas biliverdin is metabolized into bilirubin. Heme oxygenase consists of three isoforms, the inducible heme oxygenase-1, also known as heat shock protein 32, and two constitutive isoforms, heme oxygenase-2, and heme oxygenase-3. Heme oxygenase-1 activity has been shown to provide potent cytoprotective effects against a variety of agents causing oxidative stress in vivo and in vitro (297). This finding is also supported by recent observations from heme oxygenase-1 deficient mice and humans exhibiting increased susceptibility to oxidative stress among other abnormalities (298, 299).
Heme oxygenase-1 is rapidly upregulated on reperfusion, and its overexpression has been shown to confer marked cytoprotection against ischemia–reperfusion injury. Indeed, after a period of myocardial ischemia, transgenic mice overexpressing heme oxygenase-1 have better cardiac function and reduced infarct size when compared with wild-type mice, whereas heterozygous (HO-1+/-) mice with a 40% reduction in the expression of heme oxygenase-1 display reduced ventricular recovery and increased infarct size when compared with wild-type mice (300, 301). Similar findings have been observed in a liver model of ischemia–reperfusion injury when the expression of heme oxygenase-1 was induced by cobalt protoporphyrin or by adenoviral-mediated heme oxygenase-1 gene transfer (302).
The mechanism by which selective overexpression of heme oxygenase-1 confers protection against ischemia–reperfusion injury remains poorly understood and may be mediated by each of the three by-products generated by the enzyme. Free iron activates the production of ferritin, which may mediate cytoprotection against ischemia–reperfusion injury (303). Bilirubin is a known antioxidant that has been shown to protect isolated perfused rat hearts when heme oxygenase-1 was inhibited (304). Finally, carbon monoxide has recently been shown to protect the lung from ischemia–reperfusion injury through suppression of the antifibrinolytic pathway (78).
Carbon monoxide, like NO, is a messenger gas molecule that can regulate vasomotor tone through the production of cyclic 3'-5'-guanosine monophosphate (305). However, increasing evidence suggests that carbon monoxide is an extremely potent antiinflammatory and antiapoptotic molecule that mediates its cytoprotective effect through the activation of the mitogen-activated protein kinase pathway, independent of the NO/cyclic 3'-5'-guanosine monophosphate pathway (306). The administration of low levels of inhaled carbon monoxide has been shown to decrease lung inflammation induced by ischemia, hyperoxia, and aeroallergen (78, 307, 308). The levels of inhaled carbon monoxide in these studies ranged between 50 and 500 parts per million, which appears to be significantly lower than the known toxic level of carbon monoxide (297).
The effect of heme oxygenase-1 and its metabolites derives from a fine balance between cytoprotection and cytotoxicity. Indeed, carbon monoxide and bilirubin are known to be potentially toxic by, respectively, dissociating oxygen from hemoglobin and by causing kernicterus (309). In addition, overexpression of heme oxygenase-1 may be associated with an excessive accumulation of free iron, which may catalyze the formation of hydroxyl radical through the Fenton reaction, and result in increased oxidative stress (310). Future studies are required to determine the role of manipulation of this novel pathway in protecting the lung from ischemia–reperfusion injury.
Preconditioning.
Tissues exposed to one insult can develop tolerance to a subsequent injury. This biological adaptation forms the basis of the concept of preconditioning. Various types of preconditioning have been used in vivo to protect the lung from ischemia–reperfusion injury. For instance, short periods of ischemia (ischemic preconditioning) (311–314), increased temperature (hyperthermic preconditioning) (315, 316), and administration of pharmacologic agents (chemical preconditioning) (317, 318) have been shown to be successful in reducing lung injury in most cases (319).
The mechanism by which preconditioning confers protection is not well understood. Hyperthermia (approximately 5°C above normal temperature) was initially shown to upregulate the synthesis of a family of proteins, named heat shock proteins that confer protection against a variety of stresses, including ischemia–reperfusion injury (320). Although ischemic preconditioning and some cytoprotective agents have also been shown to upregulate the production of heat shock protein, the mechanism that renders the organ resistant to ischemia–reperfusion injury is certainly more complex and involves other molecules (321). Recent studies have incriminated reactive oxygen species, ATP-sensitive potassium channel openers, protein kinase C, protein tyrosine kinase, and nuclear factor-B as potential intracellular signal transduction pathways of ischemic preconditioning (322–324). Currently, ischemic preconditioning has been shown to be effective clinically in hepatic resection (325) and in coronary artery bypass graft surgery (326), but its role remains unproven in clinical lung transplantation.
Gene therapy.
The use of gene therapy in the transplantation setting is potentiated because immunosuppressive therapy allows effective and repeated transfection with current generation of viral vectors (327, 328). Multiple strategies have been used experimentally to transfect donor lungs. Genes have been administered to the donor before lung retrieval (329), on the back table during the cold ischemic time (330, 331), or to the recipient after reperfusion (332). They have been delivered intravascularly (333), intramuscularly (332), or transtracheally (329) in a naked form (334) or with the help of a vector, either viral (335) or nonviral (336).
We have demonstrated that transfection of the donor lung is possible through the transtracheal route using a second-generation adenoviral vector without contaminating other organs such as the heart, liver, or kidneys (329). Because the transfection rate is significantly decreased at cold temperature (337, 330), this mode of administration is useful in that it allows for efficient transfection before retrieving and cooling the lungs. Transtracheal administration of the gene coding for the antiinflammatory cytokine, human IL-10, to the donor 12 to 24 hours before lung retrieval reduces ischemia–reperfusion injury and improves lung function in a rat single lung transplant model (335, 338). IL-10 is an antiinflammatory cytokine that exerts antiinflammatory and immunosupressive effects on a large variety of cells including macrophages, lymphocytes, and neutrophils, and it has been shown to be beneficial in various models of ischemia–reperfusion injury (339). We are currently performing similar experiments in large animal models with endoscopic delivery of adenoviral-mediated human IL-10 gene to the donor (340). Once optimal gene delivery to large animals can be achieved, human lung protection from ischemia–reperfusion and immunologic injury by gene therapy may soon be possible.
As researches continue to improve our understanding of the mechanisms of injury related to lung preservation and as the genes that control these processes are identified, we will move closer to the ultimate strategy in preservation-related lung injury. Gene-based therapy promises the exciting potential to genetically modify organs to withstand the stresses of the transplant process.
Better understanding of the mechanisms of ischemia–reperfusion
injury, improvement in the technique of lung preservation, and
the recent introduction of a new preservation solution specifically
developed for the lungs have helped to reduce the incidence
of ischemia–reperfusion–induced lung injury and
the development of primary graft failure after lung transplantation.
In the future, the development of new agents and their application
in prospective clinical trials are to be expected to prevent
the occurrence of this potentially devastating complication
and to further improve the success of lung transplantation.
One of the major upcoming challenges will be to improve the number of donor lungs available for transplantation. Although the number of patients on the waiting list is constantly increasing, only 10 to 30% of the donor lungs are currently used for transplantation. Hence, the development of new strategies to repair and improve the quality of the lungs could have a tremendous impact on the number of transplants performed. In addition, an improved understanding of the mechanisms involved during lung preservation may help to elucidate the potential link between acute lung injury and chronic graft dysfunction. In the future, genetic analysis using novel technologies such as microarray analysis will help to determine which genes play a role in the transplantation process. Hopefully, this will provide new insights into the mechanisms of injury and reveal potential new strategies to improve lung preservation.
Received in original form July 8, 2002; accepted in final form December 3, 2002
- Hertz M, Taylor D, Trulock E, Boucek M,Mohacsi P, Edwards L, Keck B. The Registry of the International Society for Heart and Lung Transplantation: nineteenth official report: 2002. J Heart Lung Transplant 2002;21:950–970.
- King RC, Binns OA, Rodriguez F, Kanithanon RC, Daniel TM, Spotnitz WD, Tribble CG, Kron IL. Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. Ann Thorac Surg 2000;69:1681–1685.
- Fiser SM, Tribble CG, Long SM, Kaza AK, Kern JA, Jones DR, Robbins MK, Kron IL. Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome. Ann Thorac Surg 2002;73:1041–1047.
- Ware LB, Wang Y, Fang X, Warnock M, Sakuma T, Hall TS, Matthay M. Assessment of lungs rejected for transplantation and implications for donor selection. Lancet 2002;360:619–620.
- Fujimura S, Handa M, Kondo T, Ichinose T, Shiraishi Y, Nakada T. Successful 48-hour simple hypothermic preservation of canine lung transplants. Transplant Proc 1987;19:1334–1336.
- Keshavjee SH, Yamazaki F, Cardoso PF, McRitchie DI, Patterson GA, Cooper JD. A method for safe twelve-hour pulmonary preservation. J Thorac Cardiovasc Surg 1989;98:529–534.
- Meyers BF, Sundt TM, Henry S, Trulock EP, Guthrie T, Cooper JD, Patterson GA. Selective use of extracorporeal membrane oxygenation is warranted after lung transplantation. J Thorac Cardiovasc Surg 2000;120:20–26.
- Fiser SM, Kron IL, McLendon Long S, Kaza AK, Kern JA, Tribble CG. Early intervention after severe oxygenation elevation improves survival following lung transplantation. J Heart Lung Transplant 2001;20:631–636.
- Sundaresan S, Trachiotis GD, Aoe M, Patterson GA, Cooper JD. Donor lung procurement: assessment and operative technique. Ann Thorac Surg 1993;56:1409–1413.
- Sundaresan S, Semenkovich J, Ochoa L, Richardson G, Trulock EP, Cooper JD, Patterson GA. Successful outcome of lung transplantation is not compromised by the use of marginal donor lungs. J Thorac Cardiovasc Surg 1995;109:1075–1079.
- Kron IL, Tribble CG, Kern JA, Daniel TM, Rose CE, Truwit JD, Blackbourne LH, Bergin JD. Successful transplantation of marginally acceptable thoracic organs. Ann Surg 1993;217:518–522.
- Bhorade SM, Vigneswaran W, McCabe MA, Garrity ER. Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation. J Heart Lung Transplant 2000;19:1199–1204.
- Gabbay E, Williams TJ, Griffiths AP, Macfarlane LM, Kotsimbos TC, Esmore DS, Snell GI. Maximizing the utilization of donor organs offered for lung transplantation. Am J Respir Crit Care Med 1999;160:265–271.
- Pierre AF, Sekine Y, Hutcheon MA, Waddell TK, Keshavjee SH. Marginal donor lungs: a reassessment. J Thorac Cardiovasc Surg 2002;123:421–428.
- Kusaka M, Pratschke J, Wilhelm MJ, Ziai F, Zandi-Nejad K, Mackenzie HS, Hancock WW, Tilney NL. Activation of inflammatory mediators in rat renal isografts by donor brain death. Transplantation 2000;69:405–410.
- Bittner HB, Kendall SW, Chen EP, Craig D, Van Trigt P. The effects of brain death on cardiopulmonary hemodynamics and pulmonary blood flow characteristics. Chest 1995;108:1358–1363.
- Mertes PM, el Abassi K, Jaboin Y, Burtin P, Pinelli G, Carteaux JP, Burlet C, Boulange M, Villemot JP. Changes in hemodynamic and metabolic parameters following induced brain death in the pig. Transplantation 1994;58:414–418.
- Follette DM, Rudich SM, Babcock WD. Improved oxygenation and increased lung donor recovery with high-dose steroid administration after brain death. J Heart Lung Transplant 1998;17:423–429.
- Kim YS, Lim CS, Kim S, Lee JS, Lee S, Kim ST, Kim HJ, Chae DW. Cadaveric renal allograft at the time of implantation has the similar immunological features with the rejecting allograft. Transplantation 2000;70:1080–1085.
- Schwarz C, Regele H, Steininger R, Hansmann C, Mayer G, Oberbauer R. The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction. Transplantation 2001;71:1666–1670.
- Koo DD, Welsh KI, McLaren AJ, Roake JA, Morris PJ, Fuggle SV. Cadaver versus living donor kidneys: impact of donor factors on antigen induction before transplantation. Kidney Int 1999;56:1551–1559.
- Fisher AJ, Donnelly SC, Hirani N, Haslett C, Strieter RM, Dark JH, Corris PA. Elevated levels of interleukin-8 in donor lungs is associated with early graft failure after lung transplantation. Am J Respir Crit Care Med 2001;163:259–265.
- de Perrot M, Sekine Y, Fischer S, Waddell TK, McRae K, Liu M, Wigle DA, Keshavjee S. Interleukin-8 release during early reperfusion predicts graft function in human lung transplantation. Am J Respir Crit Care Med 2002;165:211–215.
- Clavien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts: an overview and synthesis of current studies. Transplantation 1992;53:957–978.
- McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159–163.
- Al Mehdi AB, Shuman H, Fisher AB. Intracellular generation of reactive oxygen species during nonhypoxic lung ischemia. Am J Physiol 1997;272:L294–L300.
- Kelly RF. Current strategies in lung preservation. J Lab Clin Med 2000;136:427–440.
- Date H, Matsumura A, Manchester JK, Obo H, Lima O, Cooper JM, Sundaresan S, Lowry OH, Cooper JD. Evaluation of lung metabolism during successful twenty-four-hour canine lung preservation. J Thorac Cardiovasc Surg 1993;105:480–491.
- Fisher AB, Dodia C, Tan ZT, Ayene I, Eckenhoff RG. Oxygen-dependent lipid peroxidation during lung ischemia. J Clin Invest 1991;88:674–679.
- Eckenhoff RG, Dodia C, Tan Z, Fisher AB. Oxygen-dependent reperfusion injury in the isolated rat lung. J Appl Physiol 1992;72:1454–1460.
- Fisher AB, Dodia C. Lung as a model for evaluation of critical intracellular PO2 and PCO. Am J Physiol 1981;241:E47–E50.
- Zhao G, Al Mehdi AB, Fisher AB. Anoxia-reoxygenation versus ischemia in isolated rat lungs. Am J Physiol 1997;273:L1112–L1117.
- Kennedy TP, Rao NV, Hopkins C, Pennington L, Tolley E, Hoidal JR. Role of reactive oxygen species in reperfusion injury of the rabbit lung. J Clin Invest 1989;83:1326–1335.
- Al Mehdi AB, Zhao G, Dodia C, Tozawa K, Costa K, Muzykantov V, Ross C, Blecha F, Dinauer M, Fisher AB. Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+. Circ Res 1998;83:730–737.
- Lansman JB. Endothelial mechanosensors: going with the flow. Nature 1988;331:481–482.
- Al Mehdi AB, Zhao G, Fisher AB. ATP-independent membrane depolarization with ischemia in the oxygen-ventilated isolated rat lung. Am J Respir Cell Mol Biol 1998;18:653–661.
- Henderson LM, Chappell JB, Jones OT. Superoxide generation by the electrogenic NADPH oxidase of human neutrophils is limited by the movement of a compensating charge. Biochem J 1988;255:285–290.
- Kitagawa S, Johnston RB Jr. Relationship between membrane potential changes and superoxide-releasing capacity in resident and activated mouse peritoneal macrophages. J Immunol 1985;135:3417–3423.
- Ware LB, Golden JA, Finkbeiner WE, Matthay MA. Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation. Am J Respir Crit Care Med 1999;159:980–988.
- Wang LS, Yoshikawa K, Miyoshi S, Nakamoto K, Hsieh CM, Yamazaki F, Guerreiro Cardoso PF, Schaefers HJ, Brito J, Keshavjee S, et al. The effect of ischemic time and temperature on lung preservation in a simple ex vivo rabbit model used for functional assessment. J Thorac Cardiovasc Surg 1989;98:333–342.
- Sugita M, Suzuki S, Kondo T, Noda M, Fujimura S. Transalveolar fluid absorption ability in rat lungs preserved with Euro-Collins solution and EP4 solution. Transplantation 1999;67:349–354.
- Yokomise H, Ueno T, Yamazaki F, Keshavjee S, Slutsky A, Patterson GA. The effect and optimal time of administration of verapamil on lung preservation. Transplantation 1990;49:1039–1043.
- Pickford MA, Gower JD, Dore C, Fryer PR, Green CJ. Lipid peroxidation and ultrastructural changes in rat lung isografts after single-passage organ flush and 48-hour cold storage with and without one-hour reperfusion in vivo. Transplantation 1990;50:210–218.
- Karck M, Haverich A. Nifedipine and diltiazem reduce pulmonary edema formation during postischemic reperfusion of the rabbit lung. Res Exp Med (Berl) 1992;192:137–144.
- Zhao G, Ayene IS, Fisher AB. Role of iron in ischemia–reperfusion oxidative injury of rat lungs. Am J Respir Cell Mol Biol 1997;16:293–299.
- Huang YT, Ghio AJ, Nozik-Grayck E, Piantadosi CA. Vascular release of nonheme iron in perfused rabbit lungs. Am J Physiol Lung Cell Mol Physiol 2001;280:L474–L481.
- Bysani GK, Kennedy TP, Ky N, Rao NV, Blaze CA, Hoidal JR. Role of cytochrome P-450 in reperfusion injury of the rabbit lung. J Clin Invest 1990;86:1434–1441.
- Pratico D, Pasin M, Barry OP, Ghiselli A, Sabatino G, Iuliano L, FitzGerald GA, Violi F. Iron-dependent human platelet activation and hydroxyl radical formation: involvement of protein kinase C. Circulation 1999;99:3118–3124.
- Qayumi AK, Jamieson WR, Poostizadeh A, Germann E, Gillespie KD. Comparison of new iron chelating agents in the prevention of ischemia/reperfusion injury: a swine model of heart-lung transplantation. J Invest Surg 1992;5:115–127.
- van Jaarsveld H, Kuyl JM, Wiid NM. Ischemia/reperfusion injury is aggravated by an iron supplemented diet and is partly prevented by simultaneous antioxidant supplementation. Res Commun Mol Pathol Pharmacol 1994;86:273–285.
- Amersi F, Dulkanchainun T, Nelson SK, Farmer DG, Kato H, Zaky J, Melinek J, Shaw GD, Kupiec-Weglinski JW, Horwitz LD, et al. A novel iron chelator in combination with a P-selectin antagonist prevents ischemia/reperfusion injury in a rat liver model. Transplantation 2001;71:112–118.
- Takeyoshi I, Iwanami K, Kamoshita N, Takahashi T, Kobayashi J, Tomizawa N, Kawashima Y, Matsumoto K, Morishita Y. Effect of lazaroid U-74389G on pulmonary ischemia-reperfusion injury in dogs. J Invest Surg 2001;14:83–92.
- Tanoue Y, Morita S, Ochiai Y, Zhang QW, Hisahara M, Miyamoto K, Nishida T, Kawachi Y, Tominaga R, Yasui H. Successful twenty-four-hour canine lung preservation with lazaroid U74500A. J Heart Lung Transplant 1996;15:43–50.
- Fischer S, Cassivi SD, Xavier AM, Cardella JA, Cutz E, Edwards V, Liu M, Keshavjee S. Cell death in human lung transplantation: apoptosis induction in human lungs during ischemia and after transplantation. Ann Surg 2000;231:424–431.
- Fischer S, Maclean AA, Liu M, Cardella JA, Slutsky AS, Suga M, Moreira JF, Keshavjee S. Dynamic changes in apoptotic and necrotic cell death correlate with severity of ischemia-reperfusion injury in lung transplantation. Am J Respir Crit Care Med 2000;162:1932–1939.
- Stammberger U, Gaspert A, Hillinger S, Vogt P, Odermatt B, Weder W, Schmid RA. Apoptosis induced by ischemia and reperfusion in experimental lung transplantation. Ann Thorac Surg 2000;69:1532–1536.
- Denecker G, Vercammen D, Declercq W, Vandenabeele P. Apoptotic and necrotic cell death induced by death domain receptors. Cell Mol Life Sci 2001;58:356–370.
- Kuwano K, Hara N. Signal transduction pathways of apoptosis and inflammation induced by the tumor necrosis factor receptor family. Am J Respir Cell Mol Biol 2000;22:147–149.
- Daemen MA, van't Veer C, Denecker G, Heemskerk VH, Wolfs TG, Clauss M, Vandenabeele P, Buurman WA. Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation. J Clin Invest 1999;104:541–549.
- Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation 1998;97:276–281.
- Hartmann A. Antiapoptotic agents in brain ischemia. N Engl J Med 2000;342:823.
- Fischer S, de Perrot M, Liu M, MacLean AA, Cardella JA, Imai Y, Suga M, Keshavjee S. IL-10 gene transfection of donor lungs ameliorates post-transplant cell death by a switch from cellular necrosis to apoptosis. J Thorac Cardiovasc Surg (In press)
- Minamiya Y, Tozawa K, Kitamura M, Saito S, Ogawa J. Platelet-activating factor mediates intercellular adhesion molecule-1-dependent radical production in the nonhypoxic ischemia rat lung. Am J Respir Cell Mol Biol 1998;19:150–157.
- Moore TM, Khimenko P, Adkins WK, Miyasaka M, Taylor AE. Adhesion molecules contribute to ischemia and reperfusion-induced injury in the isolated rat lung. J Appl Physiol 1995;78:2245–2252.
- Naka Y, Toda K, Kayano K, Oz MC, Pinsky JD. Failure to express the P-selectin gene or P-selectin blockade confers early pulmonary protection after lung ischemia or transplantation. Proc Natl Acad Sci USA 1997;94:757–761.
- Kapelanski DP, Iguchi A, Niles SD, Mao HZ. Lung reperfusion injury is reduced by inhibiting a CD18-dependent mechanism. J Heart Lung Transplant 1993;12:294–306.
- DeMeester SR, Molinari MA, Shiraishi T, Okabayashi K, Manchester JK, Wick MR, Cooper JD, Patterson GA. Attenuation of rat lung isograft reperfusion injury with a combination of anti-ICAM-1 and anti-beta2 integrin monoclonal antibodies. Transplantation 1996;62:1477–1485.
- Steinberg JB, Mao HZ, Niles SD, Jutila MA, Kapelanski DP. Survival in lung reperfusion injury is improved by an antibody that binds and inhibits L- and E-selectin. J Heart Lung Transplant 1994;13:306–318.
- Demertzis S, Langer F, Graeter T, Dwenger A, Georg T, Schafers HJ. Amelioration of lung reperfusion injury. Eur J Cardiothorac Surg 1999;16:174–180.
- Reignier J, Sellak H, Lemoine R, Lubineau A, Mazmanian GM, Detruit H, Chapelier A, Herve P. Prevention of ischemia-reperfusion lung injury by sulfated Lewis(a) pentasaccharide: The Paris-Sud University Lung Transplantation Group. J Appl Physiol 1997;82:1058–1063.
- Schmid RA, Yamashita M, Boasquevisque CH, Ando K, Fujino S, Phillips L, Cooper JD, Patterson GA. Carbohydrate selectin inhibitor CY-1503 reduces neutrophil migration and reperfusion injury in canine pulmonary allografts. J Heart Lung Transplant 1997;16:1054–1061.
- Stammberger U, Hamacher J, Hillinger S, Schmid RA. sCR1sLe ameliorates ischemia/reperfusion injury in experimental lung transplantation. J Thorac Cardiovasc Surg 2000;120:1078–1084.
- Ogawa S, Gerlach H, Esposito C, Pasagian-Macaulay A, Brett J, Stern D. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium: increased monolayer permeability and induction of procoagulant properties. J Clin Invest 1990;85:1090–1098.
- Compeau CG, Ma J, DeCampos KN, Waddell TK, Brisseau GF, Slutsky AS, Rotstein OD. In situ ischemia and hypoxia enhance alveolar macrophage tissue factor expression. Am J Respir Cell Mol Biol 1994;11:446–455.
- Salvatierra A, Velasco F, Rodriguez M, Alvarez A, Lopez-Pedrera R, Ramirez R, Carracedo J, Lopez-Rubio F, Lopez-Pujol A, Guerrero R. C1-esterase inhibitor prevents early pulmonary dysfunction after lung transplantation in the dog. Am J Respir Crit Care Med 1997;155:1147–1154.
- Struber M, Hagl C, Hirt SW, Cremer J, Harringer W, Haverich A. C1-esterase inhibitor in graft failure after lung transplantation. Intensive Care Med 1999;25:1315–1318.
- Pinsky DJ, Liao H, Lawson CA, Yan SF, Chen J, Carmeliet P, Loskutoff DJ, Stern DM. Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 1998;102:919–928.
- Fujita T, Toda K, Karimova A, Yan SF, Naka Y, Yet SF, Pinsky DJ. Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis. Nat Med 2001;7:598–604.
- Okada K, Fujita T, Minamoto K, Liao H, Naka Y, Pinsky DJ. Potentiation of endogenous fibrinolysis and rescue from lung ischemia/reperfusion injury in interleukin (IL)-10-reconstituted IL-10 null mice. J Biol Chem 2000;275:21468–21476.
- Lemay S, Rabb H, Postler G, Singh AK. Prominent and sustained up-regulation of gp130-signaling cytokines and the chemokine MIP-2 in murine renal ischemia-reperfusion injury. Transplantation 2000;69:959–963.
- Gerlach J, Jorres A, Nohr R, Zeilinger K, Spatkowski G, Neuhaus P. Local liberation of cytokines during liver preservation. Transpl Int 1999;12:261–265.
- Oz MC, Liao H, Naka Y, Seldomridge A, Becker DN, Michler RE, Smith CR, Rose EA, Stern DM, Pinsky DJ. Ischemia-induced interleukin-8 release after human heart transplantation: a potential role for endothelial cells. Circulation 1995;92:II428–II432.
- Serrick C, Adoumie R, Giaid A, Shennib H. The early release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma after ischemia reperfusion injury in the lung allograft. Transplantation 1994;58:1158–1162.
- Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick JR. The Registry of the International Society for Heart and Lung Transplantation: seventeenth official report: 2000. J Heart Lung Transplant 2000;19:909–931.
- Miller EJ, Cohen AB, Matthay MA. Increased interleukin-8 concentrations in the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis. Crit Care Med 1996;24:1448–1454.
- Mueller AR, Platz KP, Haak M, Undi H, Muller C, Kottgen E, Weidemann H, Neuhaus P. The release of cytokines, adhesion molecules, and extracellular matrix parameters during and after reperfusion in human liver transplantation. Transplantation 1996;62:1118–1126.
- Sekido N, Mukaida N, Harada A, Nakanishi I, Watanabe Y, Matsushima K. Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature 1993;365:654–657.
- Tischfield JA. A reassessment of the low molecular weight phospholipase A2 gene family in mammals. J Biol Chem 1997;272:17247–17250.
- Kim DK, Fukuda T, Thompson BT, Cockrill B, Hales C, Bonventre JV. Bronchoalveolar lavage fluid phospholipase A2 activities are increased in human adult respiratory distress syndrome. Am J Physiol 1995;269:L109–L118.
- Furue S, Kuwabara K, Mikawa K, Nishina K, Shiga M, Maekawa N, Ueno M, Chikazawa Y, Ono T, Hori Y, et al. Crucial role of group IIA phospholipase A(2) in oleic acid-induced acute lung injury in rabbits. Am J Respir Crit Care Med 1999;160:1292–1302.
- Arbibe L, Koumanov K, Vial D, Rougeot C, Faure G, Havet N, Longacre S, Vargaftig BB, Bereziat G, Voelker DR, et al. Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interaction. J Clin Invest 1998;102:1152–1160.
- Koike K, Yamamoto Y, Hori Y, Ono T. Group IIA phospholipase A2 mediates lung injury in intestinal ischemia-reperfusion. Ann Surg 2000;232:90–97.
- Shen CY, Wang D, Chang ML, Hsu K. Protective effect of mepacrine on hypoxia-reoxygenation-induced acute lung injury in rats. J Appl Physiol 1995;78:225–231.
- Nagahiro I, Aoe M, Yamashita M, Date H, Andou A, Shimizu N. EPC-K1 is effective in lung preservation in an ex vivo rabbit lung perfusion model. Ann Thorac Surg 1997;63:954–959.
- Furue S, Mikawa K, Nishina K, Shiga M, Ueno M, Tomita Y, Kuwabara K, Teshirogi I, Ono T, Hori Y, et al. Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: correlation with lung surfactant protection. Crit Care Med 2001;29:719–727.
- Miotla JM, Jeffery PK, Hellewell PG. Platelet-activating factor plays a pivotal role in the induction of experimental lung injury. Am J Respir Cell Mol Biol 1998;18:197–204.
- Nagase T, Ishii S, Kume K, Uozumi N, Izumi T, Ouchi Y, Shimizu T. Platelet-activating factor mediates acid-induced lung injury in genetically engineered mice. J Clin Invest 1999;104:1071–1076.
- Corcoran PC, Wang Y, Katz NM, Rajan SS, Analouei AR, Foegh ML, Wallace RB. Platelet activating factor antagonist enhances lung preservation in a canine model of single lung allotransplantation. J Thorac Cardiovasc Surg 1992;104:66–72.
- Kawahara K, Tagawa T, Takahashi T, Akamine S, Nakamura A, Yamamoto S, Muraoka S, Tomita M. The effect of the platelet-activating factor inhibitor TCV-309 on reperfusion injury in a canine model of ischemic lung. Transplantation 1993;55:1438–1439.
- Stammberger U, Carboni GL, Hillinger S, Schneiter D, Weder W, Schmid RA. Combined treatment with endothelin- and PAF-antagonists reduces posttransplant lung ischemia/reperfusion injury. J Heart Lung Transplant 1999;18:862–868.
- Kim JD, Baker CJ, Roberts RF, Darbinian SH, Marcus KA, Quardt SM, Starnes VA, Barr ML. Platelet activating factor acetylhydrolase decreases lung reperfusion injury. Ann Thorac Surg 2000;70:423–428.
- Su M, Chi EY, Bishop MJ, Henderson WR Jr. Lung mast cells increase in number and degranulate during pulmonary artery occlusion/reperfusion injury in dogs. Am Rev Respir Dis 1993;147:448–456.
- Shimizu N, Kita T, Aoe M, Nakata M, Miyai Y, Teramoto S. Changes in levels of arachidonic acid metabolites in blood and bronchoalveolar lavage fluid after warm ischemia-reperfusion of lung. Acta Med Okayama 1991;45:417–422.
- Zamora CA, Baron DA, Heffner JE. Thromboxane contributes to pulmonary hypertension in ischemia-reperfusion lung injury. J Appl Physiol 1993;74:224–229.
- Vural KM, Liao H, Oz MC, Pinsky DJ. Effects of mast cell membrane stabilizing agents in a rat lung ischemia-reperfusion model. Ann Thorac Surg 2000;69:228–232.
- Barr ML, Carey JN, Nishanian GP, Roberts RF, Sakamaki Y, Darbinian SH, Starnes VA. Addition of a mast cell stabilizing compound to organ preservation solutions decreases lung reperfusion injury. J Thorac Cardiovasc Surg 1998;115:631–636.
- Naka Y, Marsh HC, Scesney SM, Oz MC, Pinsky DJ. Complement activation as a cause for primary graft failure in an isogeneic rat model of hypothermic lung preservation and transplantation. Transplantation 1997;64:1248–1255.
- Bishop MJ, Giclas PC, Guidotti SM, Su ML, Chi EY. Complement activation is a secondary rather than a causative factor in rabbit pulmonary artery ischemia/reperfusion injury. Am Rev Respir Dis 1991;143:386–390.
- Frank MM. Complement in the pathophysiology of human disease. N Engl Med 1987;316:1525–1530.
- Ivey CL, Williams FM, Collins PD, Jose PJ, Williams TJ. Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit: evidence for a role for C5a and interleukin-8. J Clin Invest 1995;95:2720–2728.
- Zhou W, Farrar CA, Abe K, Pratt JR, Marsh JE, Wang Y, Stahl GL, Sacks SH. Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest 2000;105:1363–1371.
- Pierre AF, Xavier AM, Liu M, Cassivi SD, Lindsay TF, Marsh HC, Slutsky AS, Keshavjee SH. Effect of complement inhibition with soluble complement receptor 1 on pig allotransplant lung function. Transplantation 1998;66:723–732.
- Schmid RA, Zollinger A, Singer T, Hillinger S, Leon-Wyss JR, Schob OM, Hogasen K, Zund G, Patterson GA, Weder W. Effect of soluble complement receptor type 1 on reperfusion edema and neutrophil migration after lung allotransplantation in swine. J Thorac Cardiovasc Surg 1998;116:90–97.
- Boscoe MJ, Goodwin AT, Amrani M, Yacoub MH. Endothelins and the lung. Int J Biochem Cell Biol 2000;32:41–62.
- Sato Y, Hogg JC, English D, van Eeden SF. Endothelin-1 changes polymorphonuclear leukocytes' deformability and CD11b expression and promotes their retention in the lung. Am J Respir Cell Mol Biol 2000;23:404–410.
- Taghavi S, Abraham D, Riml P, Paulus P, Schafer R, Klepetko W, Aharinejad S. Co-expression of endothelin-1 and vascular endothelial growth factor mediates increased vascular permeability in lung grafts before reperfusion. J Heart Lung Transplant 2002;21:600–603.
- Shennib H, Serrick C, Saleh D, Adoumie R, Stewart DJ, Giaid A. Alterations in bronchoalveolar lavage and plasma endothelin-1 levels early after lung transplantation. Transplantation 1995;59:994–998.
- Abraham D, Taghavi S, Riml P, Paulus P, Hofmann M, Baumann C, Kocher A, Klepetko W, Aharinejad S. VEGF-A and –C but not –B mediate incraesed vascular permeability in preserved lung grafts. Transplantation 2002;73:1703–1706.
- Shennib H, Lee AG, Kuang JQ, Yanagisawa M, Ohlstein EH, Giaid A. Efficacy of administering an endothelin-receptor antagonist (SB209670) in ameliorating ischemia-reperfusion injury in lung allografts. Am J Respir Crit Care Med 1998;157:1975–1981.
- Mizutani H, Minamoto K, Aoe M, Yamashita M, Date H, Andou A, Shimizu N. Expression of endothelin-1 and effects of an endothelin receptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model. J Heart Lung Transplant 1998;17:835–845.
- Shaw MJ, Shennib H, Bousette N, Ohlstein EH, Giaid A. Effect of endothelin receptor antagonist on lung allograft apoptosis and NOSII expression. Ann Thorac Surg 2001;72:386–390.
- Sommers KE, Griffith BP, Hardesty RL, Keenan RJ. Early lung allograft function in twin recipients from the same donor: risk factor analysis. Ann Thorac Surg 1996;62:784–790.
- Zwacka RM, Zhang Y, Halldorson J, Schlossberg H, Dudus L, Engelhardt JF. CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J Clin Invest 1997;100:279–289.
- Eppinger MJ, Jones ML, Deeb GM, Bolling SF, Ward PA. Pattern of injury and the role of neutrophils in reperfusion injury of rat lung. J Surg Res 1995;58:713–718.
- Fiser SM, Tribble CG, Long SM, Kaza AK, Cope JT, Laubach VE, Kern JA, Kron IL. Lung transplant reperfusion injury involves pulmonary macrophages and circulating leukocytes in a biphasic response. J Thorac Cardiovasc Surg 2001;121:1069–1075.
- Eppinger MJ, Deeb GM, Bolling SF, Ward PA. Mediators of ischemia-reperfusion injury of rat lung. Am J Pathol 1997;150:1773–1784.
- Naidu BV, Krishnadasan B, Byrne K, Farr AL, Rosengart M, Verrier ED, Mulligan MS. Regulation of chemokine expression by cyclosporine A in alveolar macrophages exposed to hypoxia and reoxygenation. Ann Thorac Surg 2002;74:899–905.
- Richter N, Raddatz G, Steinhoff G, Schafers HJ, Schlitt HJ. Transmission of donor lymphocytes in clinical lung transplantation. Transpl Int 1994;7:414–419.
- Jonsson JR, Hogan PG, Balderson GA, Ooi LL, Lynch SV, Strong RW, Powell EE. Human liver transplant perfusate: an abundant source of donor liver- associated leukocytes. Hepatology 1997;26:1111–1114.
- Schlitt HJ, Kanehiro H, Raddatz G, Steinhoff G, Richter N, Nashan B, Ringe B, Wonigeit K, Pichlmayr R. Persistence of donor lymphocytes in liver allograft recipients. Transplantation 1993;56:1001–1007.
- Navarro F, Portales P, Candon S, Pruvot FR, Pageaux G, Fabre JM, Domergue J, Clot J. Natural killer cell and alphabeta and gammadelta lymphocyte traffic into the liver graft immediately after liver transplantation. Transplantation 2000;69:633–639.
- Navarro F, Portales P, Pageaux JP, Perrigault PF, Fabre JM, Domergue J, Clot J. Activated sub-populations of lymphocytes and natural killer cells in normal liver and liver grafts before transplantation. Liver 1998;18:259–263.
- Le Moine O, Louis H, Demols A, Desalle F, Demoor F, Quertinmont E, Goldman M, Deviere J. Cold liver ischemia-reperfusion injury critically depends on liver T cells and is improved by donor pretreatment with interleukin 10 in mice. Hepatology 2000;31:1266–1274.
- Burne MJ, Daniels F, El Ghandour A, Mauiyyedi S, Colvin RB, O'Donnell MP, Rabb H. Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest 2001;108:1283–1290.
- Clavien PA, Harvey PR, Sanabria JR, Cywes R, Levy GA, Strasberg SM. Lymphocyte adherence in the reperfused rat liver: mechanisms and effects. Hepatology 1993;17:131–142.
- de Perrot M, Young K, Imai Y, Fischer S, Liu M, Waddell TK, Zhang L, Keshavjee S. Involvement of donor T cells in the regulation of ischemia-reperfusion injury during lung transplantation . J Heart Lung Transplant 2002;21:163–164.
- Adoumie R, Serrick C, Giaid A, Shennib H. Early cellular events in the lung allograft. Ann Thorac Surg 1992;54:1071–1076.
- Deeb GM, Grum CM, Lynch MJ, Guynn TP, Gallagher KP, Ljungman AG, Bolling SF, Morganroth ML. Neutrophils are not necessary for induction of ischemia-reperfusion lung injury. J Appl Physiol 1990;68:374–381.
- Steimle CN, Guynn TP, Morganroth ML, Bolling SF, Carr K, Deeb GM. Neutrophils are not necessary for ischemia-reperfusion lung injury. Ann Thorac Surg 1992;53:64–72.
- Lu YT, Hellewell PG, Evans TW. Ischemia-reperfusion lung injury: contribution of ischemia, neutrophils, and hydrostatic pressure. Am J Physiol 1997;273:L46–L54.
- Hopkinson DN, Bhabra MS, Hooper TL. Pulmonary graft preservation: a worldwide survey of current clinical practice. J Heart Lung Transplant 1998;17:525–531.
- Keshavjee SH, Yamazaki F, Yokomise H, Cardoso PF, Mullen JB, Slutsky AS, Patterson GA. The role of dextran 40 and potassium in extended hypothermic lung preservation for transplantation. J Thorac Cardiovasc Surg 1992;103:314–325.
- Yamazaki F, Yokomise H, Keshavjee SH, Miyoshi S, Cardoso PF, Slutsky AS, Patterson GA. The superiority of an extracellular fluid solution over Euro-Collins' solution for pulmonary preservation. Transplantation 1990;49:690–694.
- Steen S, Sjoberg T, Massa G, Ericsson L, Lindberg L. Safe pulmonary preservation for 12 hours with low-potassium-dextran solution. Ann Thorac Surg 1993;55:434–440.
- Steen S, Kimblad PO, Sjoberg T, Lindberg L, Ingemansson R, Massa G. Safe lung preservation for twenty-four hours with Perfadex. Ann Thorac Surg 1994;57:450–457.
- Date H, Izumi S, Miyade Y, Andou A, Shimizu N, Teramoto S. Successful canine bilateral single-lung transplantation after 21-hour lung preservation. Ann Thorac Surg 1995;59:336–341.
- Sundaresan S, Lima O, Date H, Matsumura A, Tsuji H, Obo H, Aoe M, Mizuta T, Cooper JD. Lung preservation with low-potassium dextran flush in a primate bilateral transplant model. Ann Thorac Surg 1993;56:1129–1135.
- Soccal PM, Gasche Y, Pache JC, Schneuwly O, Slosman DO, Morel DR, Spiliopoulos A, Suter PM, Nicod LP. Matrix metalloproteinases correlate with alveolar-capillary permeability alteration in lung ischemia-reperfusion injury. Transplantation 2000;70:998–1005.
- Hausen B, Beuke M, Schroeder F, Poets CF, Hewitt C, DelRossi AJ, Schafers HJ. In vivo measurement of lung preservation solution efficacy: comparison of LPD, UW, EC and low K+-EC following short and extended ischemia. Eur J Cardiothorac Surg 1997;12:771–779.
- King RC, Binns OA, Kanithanon RC, Parrino PE, Reece TB, Maliszewskyj JD, Shockey KS, Tribble CG, Kron IL. Acellular low-potassium dextran preserves pulmonary function afer 48 hours of ischemia. Ann Thorac Surg 1997;64:795–800.
- Chien S, Zhang F, Niu W, Tseng MT, Gray L Jr. Comparison of University of Wisconsin, Euro-Collins, low-potassium dextran, and krebs-henseleit solutions for hypothermic lung preservation. J Thorac Cardiovasc Surg 2000;119:921–930.
- Roberts RF, Nishanian GP, Carey JN, Sakamaki Y, Starnes VA, Barr ML. A comparison of the new preservation solution Celsior to Euro-Collins and University of Wisconsin solutions in lung reperfusion injury. Transplantation 1999;67:152–155.
- Thabut G, Vinatier I, Brugiere O, Leseche G, Loirat P, Bisson A, Marty J, Fournier M, Mal H. Influence of preservation solution on early graft failure in clinical lung transplantation. Am J Respir Crit Care Med 2001;164:1204–1208.
- Xiong L, Legagneux J, Wassef M, Oubenaissa A, Detruit H, Mouas C, Menasche P. Protective effects of Celsior in lung transplantation. J Heart Lung Transplant 1999;18:320–327.
- Reignier J, Mazmanian M, Chapelier A, Alberici G, Menasche P, Weiss M, Herve P. Evaluation of a new preservation solution: Celsior in the isolated rat lung: Paris-Sud University Lung Transplatation Group. J Heart Lung Transplant 1995;14:601–604.
- Wittwer T, Wahlers T, Fehrenbach A, Elki S, Haverich A. Improvement of pulmonary preservation with Celsior and Perfadex: impact of storage time on early post-ischemic lung function. J Heart Lung Transplant 1999;18:1198–1201.
- Wittwer T, Fehrenbach A, Meyer D, Brandes H, Albes J, Richter J, Wahlers T. Retrograde flush perfusion with low-potassium solutions for improvement of experimental pulmonary preservation. J Heart Lung Transplant 2000;19:976–983.
- Keshavjee SH, McRitchie DI, Vittorini T, Rotstein OD, Slutsky AS, Patterson GA. Improved lung preservation with dextran 40 is not mediated by a superoxide radical scavenging mechanism. J Thorac Cardiovasc Surg 1992;103:326–328.
- Sasaki S, McCully JD, Alessandrini F, LoCicero J III. Impact of initial flush potassium concentration on the adequacy of lung preservation. J Thorac Cardiovasc Surg 1995;109:1090–1095.
- Kimblad PO, Sjoberg T, Massa G, Solem JO, Steen S. High potassium contents in organ preservation solutions cause strong pulmonary vasocontraction. Ann Thorac Surg 1991;52:523–528.
- Bando T, Albes JM, Fehrenbach H, Nusse T, Schafers HJ, Wahlers T. Influence of the potassium concentration on functional and structural preservation of the lung: where is the optimum? J Heart Lung Transplant 1998;17:715–724.
- Spaggiari L, Bobbio P. Dextran 40 at 2% versus 5% in low-potassium solutions: which is best? Ann Thorac Surg 1994;58:1784–1786.
- Schneuwly OD, Licker M, Pastor CM, Schweizer A, Slosman DO, Kapanci Y, Nicod LP, Robert J, Spiliopoulos A, Morel DR. Beneficial effects of leukocyte-depleted blood and low-potassium dextran solutions on microvascular permeability in preserved porcine lung. Am J Respir Crit Care Med 1999;160:689–697.
- Sakamaki F, Hoffmann H, Munzing S, Krombach F, Messmer K, Schildberg FW. Effects of lung preservation solutions on PMN activation in vitro. Transpl Int 1999;12:113–121.
- Maccherini M, Keshavjee SH, Slutsky AS, Patterson GA, Edelson JD. The effect of low-potassium-dextran versus Euro-Collins solution for preservation of isolated type II pneumocytes. Transplantation 1991;52:621–626.
- Carbognani P, Rusca M, Solli P, Spaggiari L, Alessandrini F, Ferrari C, Cattelani L, Dal Corso H, Bobbio P. Pneumocytes type II ultrastructural modifications after storage in preservation solutions for transplantation. Eur Surg Res 1997;29:319–326.
- Suzuki S, Inoue K, Sugita M, Tsubochi H, Kondo T, Fujimura S. Effects of EP4 solution and LPD solution vs Euro-Collins solution on Na(+)/K(+)-ATPase activity in rat alveolar type II cells and human alveolar epithelial cell line A549 cells. J Heart Lung Transplant 2000;19:887–893.
- Sakamaki F, Hoffmann H, Muller C, Dienemann H, Messmer K, Schildberg FW. Reduced lipid peroxidation and ischemia-reperfusion injury after lung transplantation using low-potassium dextran solution for lung preservation. Am J Respir Crit Care Med 1997;156:1073–1081.
- Struber M, Hohlfeld JM, Fraund S, Kim P, Warnecke G, Haverich A. Low-potassium dextran solution ameliorates reperfusion injury of the lung and protects surfactant function. J Thorac Cardiovasc Surg 2000;120:566–572.
- Hopkinson DN, Odom NJ, Bridgewater BJ, Hooper TL. Comparison of saccharides as osmotic impermeants during hypothermic lung graft preservation. Transplantation 1996;61:1667–1671.
- Hopkinson DN, Odom NJ, Bridgewater BJ, Hooper TL. University of Wisconsin solution for lung graft preservation: which components are important? J Heart Lung Transplant 1994;13:990–997.
- Fischer S, Hopkinson D, Liu M, Keshavjee S. Raffinose improves the function of rat pulmonary grafts stored for twenty-four hours in low-potassium dextran solution. J Thorac Cardiovasc Surg 2000;119:488–492.
- Fischer S, Hopkinson D, Liu M, Maclean AA, Edwards V, Cutz E, Keshavjee S. Raffinose improves 24-hour lung preservation in low potassium dextran glucose solution: a histologic and ultrastructural analysis. Ann Thorac Surg 2001;71:1140–1145.
- Fischer S, Matte-Martyn A, de Perrot M, Waddell TK, Sekine Y, Hutcheon M, Keshavjee S. Low-potassium dextran preservation solution improves lung function after human lung transplantation. J Thorac Cardiovasc Surg 2001;121:594–596.
- Struber M, Wilhelmi M, Harringer W, Niedermeyer J, Anssar M, Kunsebeck A, Schmitto JD, Haverich A. Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation. Eur J Cardiothorac Surg 2001;19:190–194.
- Muller C, Furst H, Reichenspurner H, Briegel J, Groh J, Reichart B. Lung procurement by low-potassium dextran and the effect on preservation injury: Munich Lung Transplant Group. Transplantation 1999;68:1139–1143.
- Haverich A, Aziz S, Scott WC, Jamieson SW, Shumway NE. Improved lung preservation using Euro-Collins solution for flush-perfusion. Thorac Cardiovasc Surg 1986;34:368–376.
- Sasaki M, Muraoka R, Chiba Y, Hiramatu Y. Influence of pulmonary arterial pressure during flushing on lung preservation. Transplantation 1996;61:22–27.
- Tanaka H, Chiba Y, Sasaki M, Matsukawa S, Muraoka R. Relationship between flushing pressure and nitric oxide production in preserved lungs. Transplantation 1998;65:460–464.
- Andrade RS, Wangensteen OD, Jo JK, Tsai MY, Bolman RM III. Effect of hypothermic pulmonary artery flushing on capillary filtration coefficient. Transplantation 2000;70:267–271.
- Kimblad PO, Sjoberg T, Steen S. Pulmonary vascular resistance related to endothelial function after lung transplantation. Ann Thorac Surg 1994;58:416–420.
- Kimblad PO, Massa G, Sjoberg T, Steen S. Endothelium-dependent relaxation in pulmonary arteries after lung preservation and transplantation. Ann Thorac Surg 1993;56:1329–1333.
- Wang LS, Nakamoto K, Hsieh CM, Miyoshi S, Cooper JD. Influence of temperature of flushing solution on lung preservation. Ann Thorac Surg 1993;55:711–715.
- Chiang CH, Wu K, Yu CP, Yan HC, Perng WC, Wu CP. Hypothermia and prostaglandin E(1) produce synergistic attenuation of ischemia-reperfusion lung injury. Am J Respir Crit Care Med 1999;160:1319–1323.
- Albes JM, Fischer F, Bando T, Heinemann MK, Scheule A, Wahlers T. Influence of the perfusate temperature on lung preservation: is there an optimum? Eur Surg Res 1997;29:5–11.
- Wittwer T, Wahlers T, Fehrenbach A, Cornelius JF, Elki S, Ochs M, Fehrenbach H, Albes J, Haverich A, Richter J. Combined use of prostacyclin and higher perfusate temperatures further enhances the superior lung preservation by Celsior solution in the isolated rat lung. J Heart Lung Transplant 1999;18:684–692.
- Fehrenbach H, Riemann D, Wahlers T, Hirt SW, Haverich A, Richter J. Scanning and transmission electron microscopy of human donor lungs: fine structure of the pulmonary parenchyma following preservation and ischemia. Acta Anat (Basel) 1994;151:220–231.
- Muller C, Hoffmann H, Bittmann I, Isselhard W, Messmer K, Dienemann H, Schildberg FW. Hypothermic storage alone in lung preservation for transplantation: a metabolic, light microscopic, and functional analysis after 18 hours of preservation. Transplantation 1997;63:625–630.
- The Toronto Lung Transplant Group. Experience with single-lung transplantation for pulmonary fibrosis. JAMA 1988;259:2258–2262.
- Steen S, Sjoberg T, Ingemansson R, Lindberg L. Efficacy of topical cooling in lung preservation: is a reappraisal due? Ann Thorac Surg 1994;58:1657–1663.
- Haverich A, Scott WC, Jamieson SW. Twenty years of lung preservation: a review. J Heart Transplant 1985;4:234–240.
- Date H, Matsumura A, Manchester JK, Cooper JM, Lowry OH, Cooper JD. Changes in alveolar oxygen and carbon dioxide concentration and oxygen consumption during lung preservation: the maintenance of aerobic metabolism during lung preservation. J Thorac Cardiovasc Surg 1993;105:492–501.
- Akashi A, Nakahara K, Kamiike W, Matsumura A, Hatanaka N, Kawashima Y, Yoshida Y, Tagawa K. Attenuation of warm ischemic injury of rat lung by inflation with room air: assessment of cellular components and the surfactant in the bronchoalveolar lavage fluid in relation to changes in cellular adenosine triphosphate. Transplantation 1993;55:24–30.
- Fukuse T, Hirata T, Nakamura T, Kawashima M, Hitomi S, Wada H. Influence of deflated and anaerobic conditions during cold storage on rat lungs. Am J Respir Crit Care Med 1999;160:621–627.
- DeCampos KN, Keshavjee S, Liu M, Slutsky AS. Optimal inflation volume for hypothermic preservation of rat lungs. J Heart Lung Transplant 1998;17:599–607.
- Sakuma T, Tsukano C, Ishigaki M, Nambu Y, Osanai K, Toga H, Takahashi K, Ohya N, Kurihara T, Nishio M, et al. Lung deflation impairs alveolar epithelial fluid transport in ischemic rabbit and rat lungs. Transplantation 2000;69:1785–1793.
- Baretti R, Bitu-Moreno J, Beyersdorf, Matheis G, Francischetti I, Kreitmayr B. Distribution of lung preservation solutions in parenchyma and airways: influence of atelectasis and route of delivery. J Heart Lung Transplant 1995;14:80–91.
- Unruh H, Hoppensack M, Oppenheimer L. Vascular properties of canine lungs perfused with Eurocollins solution and prostacyclin. Ann Thorac Surg 1990;49:292–298.
- Dos Santos CC, Slutsky AS. Invited review: mechanisms of ventilator-induced lung injury: a perspective. J Appl Physiol 2000;89:1645–1655.
- Haniuda M, Hasegawa S, Shiraishi T, Dresler CM, Cooper JD, Patterson GA. Effects of inflation volume during lung preservation on pulmonary capillary permeability. J Thorac Cardiovasc Surg 1996;112:85–93.
- Aoe M, Okabayashi K, Cooper JD, Patterson GA. Hyperinflation of canine lung allografts during storage increases reperfusion pulmonary edema. J Thorac Cardiovasc Surg 1996;112:94–102.
- Kayano K, Toda K, Naka Y, Pinsky DJ. Identification of optimal conditions for lung graft storage with Euro-Collins solution by use of a rat orthotopic lung transplant model. Circulation 1999;100:II257–II261.
- Weder W, Harper B, Shimokawa S, Miyoshi S, Date H, Schreinemakers H, Egan T, Cooper JD. Influence of intraalveolar oxygen concentration on lung preservation in a rabbit model. J Thorac Cardiovasc Surg 1991;101:1037–1043.
- Haniuda M, Dresler CM, Mizuta T, Cooper JD, Patterson GA. Free radical-mediated vascular injury in lungs preserved at moderate hypothermia. Ann Thorac Surg 1995;60:1376–1381.
- Date H, Lima O, Matsumura A, Tsuji H, d'Avignon DA, Cooper JD. In a canine model, lung preservation at 10 degrees C is superior to that at 4 degrees C: a comparison of two preservation temperatures on lung function and on adenosine triphosphate level measured by phosphorus 31-nuclear magnetic resonance. J Thorac Cardiovasc Surg 1992;103:773–780.
- Ueno T, Yokomise H, Oka T, Puskas J, Mayer E, Slutsky AS, Patterson GA. The effect of PGE1 and temperature on lung function following preservation. Transplantation 1991;52:626–630.
- Mayer E, Puskas JD, Cardoso PF, Shi S, Slutsky AS, Patterson GA. Reliable eighteen-hour lung preservation at 4 degrees and 10 degrees C by pulmonary artery flush after high-dose prostaglandin E1 administration. J Thorac Cardiovasc Surg 1992;103:1136–1142.
- Kirk AJ, Colquhoun IW, Dark JH. Lung preservation: a review of current practice and future directions. Ann Thorac Surg 1993;56:990–1000.
- Sarsam MA, Yonan NA, Deiraniya AK, Rahman AN. Retrograde pulmonaryplegia for lung preservation in clinical transplantation: a new technique. J Heart Lung Transplant 1993;12:494–498.
- Varela A, Montero C, Cordoba M, Serrano-Fiz S, Burgos R, Tellez JC, Tebar E, Tellez G, Ugarte J. Clinical experience with retrograde lung preservation. Transpl Int 1996;9:S296–S298.
- Struber M, Hohlfeld JM, Kofidis T, Warnecke G, Niedermeyer J, Sommer SP, Haverich A. Surfactant function in lung transplantation after 24 hours of ischemia: advantage of retrograde flush perfusion for preservation. J Thorac Cardiovasc Surg 2002;123:98–103.
- Varela A, Montero CG, Cordoba M, Antequera A, Perez M, Tabuenca MJ, Ortiz BJ, Tendillo FJ, Mascias A, Santos M, et al. Improved distribution of pulmonary flush solution to the tracheobronchial wall in pulmonary transplantation. Eur Surg Res 1997;29:1–4.
- Chen CZ, Gallagher RC, Ardery P, Dyckman W, Donabue S, Low HB. Retrograde flush and cold storage for twenty-two to twenty-five hours lung preservation with and without prostaglandin E1. J Heart Lung Transplant 1997;16:658–666.
- Varela A, Cordoba M, Serrano-Fiz S, Burgos R, Montero CG, Tellez G, Novoa N, Castedo E, Tebar E, Tellez J, et al. Early lung allograft function after retrograde and antegrade preservation. J Thorac Cardiovasc Surg 1997;114:1119–1120.
- Venuta F, Rendina EA, Bufi M, Della RG, De Giacomo T, Costa MG, Pugliese F, Coccia C, Ciccone AM, Coloni GF. Preimplantation retrograde pneumoplegia in clinical lung transplantation. J Thorac Cardiovasc Surg 1999;118:107–114.
- Parrott NR,Forsythe JL, Matthews JN, Lennard TW, Rigg KM, Proud G, Taylor RM. Late perfusion: a simple remedy for renal allograft primary nonfunction. Transplantation 1990;49:913–915.
- Moriyasu K, McKeown PP, Novitzky D, Snow TR. Beneficial effect of initial warm crystalloid reperfusion in 6-hour lung preservation. J Heart Lung Transplant 1995;14:699–705.
- Serrick CJ, Jamjoum A, Reis A, Giaid A, Shennib H. Amelioration of pulmonary allograft injury by administering a second rinse solution. J Thorac Cardiovasc Surg 1996;112:1010–1016.
- Gao WS, Takei Y, Marzi I, Lindert KA, Caldwell-Kenkel JC, Currin RT, Tanaka Y, Lemasters JJ, Thurman RG. Carolina rinse solution: a new strategy to increase survival time after orthotopic liver transplantation in the rat. Transplantation 1991;52:417–424.
- Pierre AF, DeCampos KN, Liu M, Edwards V, Cutz E, Slutsky AS, Keshavjee SH. Rapid reperfusion causes stress failure in ischemic rat lungs. J Thorac Cardiovasc Surg 1998;116:932–942.
- Bhabra MS, Hopkinson DN, Shaw TE, Onwu N, Hooper TL. Controlled reperfusion protects lung grafts during a transient early increase in permeability. Ann Thorac Surg 1998;65:187–192.
- Clark SC, Sudarshan C, Khanna R, Roughan J, Flecknell PA, Dark JH. Controlled reperfusion and pentoxifylline modulate reperfusion injury after single lung transplantation. J Thorac Cardiovasc Surg 1998;115:1335–1341.
- Halldorsson A, Kronon M, Allen BS, Bolling KS, Wang T, Rahman S, Feinberg H. Controlled reperfusion after lung ischemia: implications for improved function after lung transplantation. J Thorac Cardiovasc Surg 1998;115:415–424.
- de Perrot M, Imai Y, Ranieri VM, Waddell TK, Liu M, McRae K, Zhang H, Slutsky AS, Keshavjee S. Impact of ventilator induced lung injury on the development of reperfusion injury in a rat lung transplant model. J Thorac Cardiovasc Surg 2002;124:1137–1144.
- McRae KM. Pulmonary transplantation. Curr Opin Anesthesiol 2000;13:53–59.
- DeCampos KN, Keshavjee S, Slutsky AS, Liu M. Alveolar recruitment prevents rapid-reperfusion-induced injury of lung transplants. J Heart Lung Transplant 1999;18:1096–1102.
- Meyer KC, Love RB, Zimmerman JJ. The therapeutic potential of nitric oxide in lung transplantation. Chest 1998;113:1360–1371.
- Liu M, Tremblay L, Cassivi SD, Bai XH, Mourgeon E, Pierre AF, Slutsky AS, Post M, Keshavjee S. Alterations of nitric oxide synthase expression and activity during rat lung transplantation. Am J Physiol Lung Cell Mol Physiol 2000;278:L1071–L1081.
- Pinsky DJ, Naka Y, Chowdhury NC, Liao H, Oz MC, Michler RE, Kubaszewski E, Malinski T, Stern DM. The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation. Proc Natl Acad Sci USA 1994;91:12086–12090.
- Marczin N, Riedel B, Gal J, Polak J, Yacoub M. Exhaled nitric oxide during lung transplantation. Lancet 1997;350:1681–1682.
- Le Cras TD, McMurtry IF. Nitric oxide production in the hypoxic lung. Am J Physiol Lung Cell Mol Physiol 2001;280:L575–L582.
- Vainikka T, Heikkila L, Kukkonen S, Toivonen HJ. L-arginine in lung graft preservation and reperfusion. J Heart Lung Transplant 2001;20:559–567.
- Shiraishi Y, Lee JR, Laks H, Waters PF, Meneshian A, Blitz A, Johnson K, Lam L, Chang PA. L-arginine administration during reperfusion improves pulmonary function. Ann Thorac Surg 1996;62:1580–1586.
- Sandera P, Hillinger S, Stammberger U, Schoedon G, Zalunardo M, Weder W, Schmid RA. 8-Br-cyclic GMP given during reperfusion improves post-transplant lung edema and free radical injury. J Heart Lung Transplant 2000;19:173–178.
- Murakami S, Bacha EA, GMazmanian GM, Detruit H, Chapelier A, Dartevelle P, Herve P. Effects of various timings and concentrations of inhaled nitric oxide in lung ischemia-reperfusion: The Paris-Sud University Lung Transplantation Group. Am J Respir Crit Care Med 1997;156:454–458.
- Bhabra MS, Hopkinson DN, Shaw TE, Hooper TL. Low-dose nitric oxide inhalation during initial reperfusion enhances rat lung graft function. Ann Thorac Surg 1997;63:339–344.
- Bacha EA, Herve P, Murakami S, Chapelier A, Mazmanian GM, de Montpreville V, Detruit H, Libert JM, Dartevelle P. Lasting beneficial effect of short-term inhaled nitric oxide on graft function after lung transplantation: Paris-Sud University Lung Transplantation Group. J Thorac Cardiovasc Surg 1996;112:590–598.
- Okabayashi K, Triantafillou AN, Yamashita M, Aoe M, DeMeester SR, Cooper JD, Patterson GA. Inhaled nitric oxide improves lung allograft function after prolonged storage. J Thorac Cardiovasc Surg 1996;112:293–299.
- Takeyoshi I, Otani Y, Yoshinari D, Kawashima Y, Ohwada S, Matsumoto K, Morishita Y. Beneficial effects of novel nitric oxide donor (FK409) on pulmonary ischemia-reperfusion injury in rats. J Heart Lung Transplant 2000;19:185–192.
- Sunose Y, Takeyoshi I, Ohwada S, Iwazaki S, Aiba M, Tomizawa N, Tsutsumi H, Oriuchi N, Matsumoto K, Morishita Y. The effect of FK409—a nitric oxide donor—on canine lung transplantation. J Heart Lung Transplant 2000;19:298–309.
- King RC, Binns OA, Kanithanon RC, Cope JT, Chun RL, Shockey KS, Tribble CG, Kron IL. Low-dose sodium nitroprusside reduces pulmonary reperfusion injury. Ann Thorac Surg 1997;63:1398–1404.
- Yamashita M, Schmid RA, Ando K, Cooper JD, Patterson GA. Nitroprusside ameliorates lung allograft reperfusion injury. Ann Thorac Surg 1996;62:791–796.
- Lockinger A, Schutte H, Walmrath D, Seeger W, Grimminger F. Protection against gas exchange abnormalities by pre-aerosolized PGE1, iloprost and nitroprusside in lung ischemia-reperfusion. Transplantation 2001;71:185–193.
- Bhabra MS, Hopkinson DN, Shaw TE, Hooper TL. Attenuation of lung graft reperfusion injury by a nitric oxide donor. J Thorac Cardiovasc Surg 1997;113:327–333.
- Kawashima M, Bando T, Nakamura T, Isowa N, Liu M, Toyokuni S, Hitomi S, Wada H. Cytoprotective effects of nitroglycerin in ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med 2000;161:935–943.
- Kayano K, Toda K, Naka Y, Okada K, Oz MC, Pinsky DJ. Superior protection in orthotopic rat lung transplantation with cyclic adenosine monophosphate and nitroglycerin-containing preservation solution. J Thorac Cardiovasc Surg 1999;118:135–144.
- Naka Y, Chowdhury NC, Liao H, Roy DK, Oz MC, Michler RE, Pinsky DJ. Enhanced preservation of orthotopically transplanted rat lungs by nitroglycerin but not hydralazine: requirement for graft vascular homeostasis beyond harvest vasodilation. Circ Res 1995;76:900–906.
- Clark SC, Sudarshan C, Roughan J, Flecknell PA, Dark JH. Modulation of reperfusion injury after single lung transplantation by pentoxifylline, inositol polyanions, and sin-1. J Thorac Cardiovasc Surg 1999;117:556–564.
- Schmid RA, Hillinger S, Walter R, Zollinger A, Stammberger U, Speich R, Schaffner A, Weder W, Schoedon G. The nitric oxide synthase cofactor tetrahydrobiopterin reduces allograft ischemia-reperfusion injury after lung transplantation. J Thorac Cardiovasc Surg 1999;118:726–732.
- Suda T, Mora BN, D'Ovidio F, Cooper JA, Hiratsuka M, Zhang W, Mohanakumar T, Patterson GA. In vivo adenovirus-mediated endothelial nitric oxide synthase gene transfer ameliorates lung allograft ischemia-reperfusion injury. J Thorac Cardiovasc Surg 2000;119:297–304.
- Chetham PM, Sefton WD, Bridges JP, Stevens T, McMurtry IF. Inhaled nitric oxide pretreatment but not posttreatment attenuates ischemia-reperfusion-induced pulmonary microvascular leak. Anesthesiology 1997;86:895–902.
- Fehrenbach A, Wittwer T, Meyer D, von Vietinghoff S, Viehover M, Fehrenbach H, Richter J, Wahlers T. Nitroglycerin alters alveolar type II cell ultrastructure after ischemia and reperfusion. J Heart Lung Transplant 2001;20:876–888.
- Hausen B, Muller P, Bahra M, Ramsamooj R, Hewitt CW. Donor pretreatment with intravenous prostacyclin versus inhaled nitric oxide in experimental lung transplantation. Transplantation 1996;62:1714–1719.
- Schutte H, Mayer K, Burger H, Witzenrath M, Gessler T, Seeger W, Grimminger F. Endogenous nitric oxide synthesis and vascular leakage in ischemic-reperfused rabbit lungs. Am J Respir Crit Care Med 2001;164:412–418.
- Bhabra MS, Hopkinson DN, Shaw TE, Hooper TL. Modulation of lung reperfusion injury by nitric oxide: impact of inspired oxygen fraction. Transplantation 1999;68:1238–1243.
- Eppinger MJ, Ward PA, Jones ML, Bolling SF, Deeb GM. Disparate effects of nitric oxide on lung ischemia-reperfusion injury. Ann Thorac Surg 1995;60:1169–1175.
- Adatia I, Lillehei C, Arnold JH, Thompson JE, Palazzo R, Fackler JC, Wessel DL. Inhaled nitric oxide in the treatment of postoperative graft dysfunction after lung transplantation. Ann Thorac Surg 1994;57:1311–1318.
- Date H, Triantafillou AN, Trulock EP, Pohl MS, Cooper JD, Patterson GA. Inhaled nitric oxide reduces human lung allograft dysfunction. J Thorac Cardiovasc Surg 1996;111:913–919.
- Hermle G, Schutte H, Walmrath D, Geiger K, Seeger W, Grimminger F. Ventilation-perfusion mismatch after lung ischemia-reperfusion: protective effect of nitric oxide. Am J Respir Crit Care Med 1999;160:1179–1187.
- Kemming GI, Merkel MJ, Schallerer A, Habler OP, Kleen MS, Haller M, Briegel J, Vogelmeier C, Furst H, Reichart B, et al. Inhaled nitric oxide (NO) for the treatment of early allograft failure after lung transplantation: Munich Lung Transplant Group. Intensive Care Med 1998;24:1173–1180.
- Macdonald P, Mundy J, Rogers P, Harrison G, Branch J, Glanville A, Keogh A, Spratt P. Successful treatment of life-threatening acute reperfusion injury after lung transplantation with inhaled nitric oxide. J Thorac Cardiovasc Surg 1995;110:861–863.
- Ardehali A, Laks H, Levine M, Shpiner R, Ross D, Watson LD, Shvartz O, Sangwan S, Waters PF. A prospective trial of inhaled nitric oxide in clinical lung transplantation. Transplantation 2001;72:112–115.
- Thabut G, Brugiere O, Leseche G, Stern JB, Fradj K, Herve P, Jebrak G, Marty J, Fournier M, Mal H. Preventive effect of inhaled nitric oxide and pentoxifylline on ischemia/reperfusion injury after lung transplantation. Transplantation 2001;71:1295–1300.
- Meade M, Granton JT, Matte-Martyn A, McRae K, Cripps PM, Weaver B, Keshavjee SH. A randomized trial of inhaled nitric oxide to prevent reperfusion injury following lung transplantation . J Heart Lung Transplant 2001;20:254–255.
- Naka Y, Roy DK, Liao H, Chowdhury NC, Michler RE, Oz MC, Pinsky DJ. cAMP-mediated vascular protection in an orthotopic rat lung transplant model: insights into the mechanism of action of prostaglandin E1 to improve lung preservation. Circ Res 1996;79:773–783.
- de Perrot M, Fischer S, Liu M, Jin R, Bai XH, Waddell TK, Keshavjee S. Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: a shift from pro- to anti-inflammatory cytokines. Transplantation 2001;72:1505–1512.
- Aoe M, Trachiotis GD, Okabayashi K, Manchester JK, Lowry OH, Cooper JD, Patterson GA. Administration of prostaglandin E1 after lung transplantation improves early graft function. Ann Thorac Surg 1994;58:655–661.
- DeCampos KN, Keshavjee S, Liu M, Slutsky AS. Prevention of rapid reperfusion-induced lung injury with prostaglandin E1 during the initial period of reperfusion. J Heart Lung Transplant 1998;17:1121–1128.
- Matsuzaki Y, Waddell TK, Puskas JD, Hirai T, Nakajima S, Slutsky AS, Patterson GA. Amelioration of post-ischemic lung reperfusion injury by prostaglandin E1. Am Rev Respir Dis 1993;148:882–889.
- Himmelreich G, Hundt K, Neuhaus P, Bechstein WO, Roissant R, Riess H. Evidence that intraoperative prostaglandin E1 infusion reduces impaired platelet aggregation after reperfusion in orthotopic liver transplantation. Transplantation 1993;55:819–826.
- Okada Y, Marchevsky AM, Kass RM, Matloff JM, Jordan SC. A stable prostacyclin analog, beraprost sodium, attenuates platelet accumulation and preservation-reperfusion injury of isografts in a rat model of lung transplantation. Transplantation 1998;66:1132–1136.
- Christie JD, Bavaria JE, Palevsky HI, Litzky L, Blumenthal NP, Kaiser LR, Kotloff RM. Primary graft failure following lung transplantation. Chest 1998;114:51–60.
- Keshavjee SH, Davis RD, Zamora MR, Schulman L, Levin J, Ryan U, Patterson GA. Inhibition of complement in human lung transplant reperfusion injury: a multicenter clinical trial . J Heart Lung Transplant 1998;13:254.
- Zamora MR, Davis RD, Keshavjee SH, Schulman L, Levin J, Ryan U, Patterson GA. Complement inhibition attenuates human lung transplant reperfusion injury: a multicenter trial. Chest 1999;116:46S.
- Rioux P. TP-10 (AVANT immunotherapeutics). Curr Opin Investig Drugs 2001;2:364–371.
- McRae K. Con: lung transplantation should not be routinely performed with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14:746–750.
- Marczin N, Royston D, Yacoub M. Pro: lung transplantation should be routinely performed with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14:739–745.
- Wittwer T, Grote M, Oppelt P, Franke U, Schaefers HJ, Wahlers T. Impact of PAF antagonist BN 52021 (Ginkolide B) on post-ischemic graft function in clinical lung transplantation. J Heart Lung Transplant 2001;20:358–363.
- Grino JM. BN 52021: a platelet activating factor antagonist for preventing post-transplant renal failure: a double-blind, randomized study: the BN 52021 Study Group in Renal Transplantation. Ann Intern Med 1994;121:345–347.
- Novick RJ, Possmayer F, Veldhuizen RA, Menkis AH, McKenzie FN. Surfactant analysis and replacement therapy: a future tool of the lung transplant surgeon? Ann Thorac Surg 1991;52:1194–1200.
- Ochs M, Nenadic I, Fehrenbach A, Albes JM, Wahlers T, Richter J, Fehrenbach H. Ultrastructural alterations in intraalveolar surfactant subtypes after experimental ischemia and reperfusion. Am J Respir Crit Care Med 1999;160:718–724.
- Andrade RS, Solien EE, Wangensteen OD, Tsai MY, Kshettry VR, Bolman RM III. Surfactant dysfunction in lung preservation. Transplantation 1995;60:536–541.
- Ochs M, Fehrenbach H, Nenadic I, Bando T, Fehrenbach A, Schepelmann D, Albes JM, Wahlers T, Richter J. Preservation of intraalveolar surfactant in a rat lung ischaemia/reperfusion injury model. Eur Respir J 2000;15:526–531.
- Veldhuizen RA, Lee J, Sandler D, Hull W, Whitsett JA, Lewis J, Possmayer F, Novick RJ. Alterations in pulmonary surfactant composition and activity after experimental lung transplantation. Am Rev Respir Dis 1993;148:208–215.
- Casals C, Varela A, Ruano ML, Valino F, Perez-Gil J, Torre N, Jorge E, Tendillo F, Castillo-Olivares JL. Increase of C-reactive protein and decrease of surfactant protein A in surfactant after lung transplantation. Am J Respir Crit Care Med 1998;157:43–49.
- Fehrenbach A, Ochs M, Warnecke T, Wahlers T, Wittwer T, Schmiedl A, Elki S, Meyer D, Richter J, Fehrenbach H. Beneficial effect of lung preservation is related to ultrastructural integrity of tubular myelin after experimental ischemia and reperfusion. Am J Respir Crit Care Med 2000;161:2058–2065.
- Ochs M, Fehrenbach H, Richter J. Ultrastructure of canine type II pneumocytes during hypothermic ischemia of the lung: a study by means of conventional and energy filtering transmission electron microscopy and stereology. Anat Rec 2001;263:118–126.
- Erasmus ME, Petersen AH, Oetomo SB, Prop J. The function of surfactant is impaired during the reimplantation response in rat lung transplants. J Heart Lung Transplant 1994;13:791–802.
- Buchanan SA, MMauney MC, Parekh VI, DeLima NF, Binns OA, Cope JT, Shockey KS, Tribble CG, Kron IL. Intratracheal surfactant administration preserves airway compliance during lung reperfusion. Ann Thorac Surg 1996;62:1617–1621.
- Hausen B, Rohde R, Hewitt CW, Schroeder F, Beuke M, Ramsamooj R, Schafers HJ, Borst HG. Exogenous surfactant treatment before and after sixteen hours of ischemia in experimental lung transplantation. J Thorac Cardiovasc Surg 1997;113:1050–1058.
- Novick RJ, MacDonald J, Veldhuizen RA, Wan F, Duplan J, Denning L, Possmayer F, Gilpin AA, Yao LJ, Bjarneson D, et al. Evaluation of surfactant treatment strategies after prolonged graft storage in lung transplantation. Am J Respir Crit Care Med 1996;154:98–104.
- Erasmus ME, Petersen AH, Hofstede G, Haagsman HP, Bambang OS, Prop J. Surfactant treatment before reperfusion improves the immediate function of lung transplants in rats. Am J Respir Crit Care Med 1996;153:665–670.
- Hohlfeld JM, Struber M, Ahlf K, Hoeper MM, Fraund S, Krug N, Warnecke G, Harringer W, Haverich A, Fabel H. Exogenous surfactant improves survival and surfactant function in ischaemia-reperfusion injury in minipigs. Eur Respir J 1999;13:1037–1043.
- Struber M, Hirt SW, Cremer J, Harringer W, Haverich A. Surfactant replacement in reperfusion injury after clinical lung transplantation. Intensive Care Med 1999;25:862–864.
- Erasmus ME, Hofstede GJ, Petersen AH, Haagsman HP, Oetomo SB, Prop J. Effects of early surfactant treatment persisting for one week after lung transplantation in rats. Am J Respir Crit Care Med 1997;156:567–572.
- Novick RJ, Veldhuizen RA, Possmayer F, Lee J, Sandler D, Lewis JF. Exogenous surfactant therapy in thirty-eight hour lung graft preservation for transplantation. J Thorac Cardiovasc Surg 1994;108:259–268.
- Otterbein LE, Choi AM. Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 2000;279:L1029–L1037.
- Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 1997;94:10925–10930.
- Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 1999;103:129–135.
- Yet SF, Tian R, Layne MD, Wang ZY, Maemura K, Solovyeva M, Ith B, Melo LG, Zhang L, Ingwall JS, et al. Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res 2001;89:168–173.
- Yoshida T, Maulik N, Ho YS, Alam J, Das DK. H(mox-1) constitutes an adaptive response to effect antioxidant cardioprotection: a study with transgenic mice heterozygous for targeted disruption of the heme oxygenase-1 gene. Circulation 2001;103:1695–1701.
- Amersi F, Buelow R, Kato H, Ke B, Coito AJ, Shen XD, Zhao D, Zaky J, Melinek J, Lassman CR, et al. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 1999;104:1631–1639.
- Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM. Ferritin: a cytoprotective antioxidant strategem of endothelium. J Biol Chem 1992;267:18148–18153.
- Clark JE, Foresti R, Sarathchandra P, Kaur H, Green CJ, Motterlini R. Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. Am J Physiol Heart Circ Physiol 2000;278:H643–H651.
- Karimova A, Pinsky DJ. The endothelial response to oxygen deprivation: biology and clinical implications. Intensive Care Med 2001;27:19–31.
- Otterbein LE, Bach FH, Alam J, Soares M, Tao LH, Wysk M, Davis RJ, Flavell RA, Choi AM. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 2000;6:422–428.
- Chapman JT, Otterbein LE, Elias JA, Choi AM. Carbon monoxide attenuates aeroallergen-induced inflammation in mice. Am J Physiol Lung Cell Mol Physiol 2001;281:L209–L216.
- Clayton CE, Carraway MS, Suliman HB, Thalmann ED, Thalmann KN, Schmechel DE, Piantadosi CA. Inhaled carbon monoxide and hyperoxic lung injury in rats. Am J Physiol Lung Cell Mol Physiol 2001;281:L949–L957.
- Choi AM. Heme oxygenase-1 protects the heart. Circ Res 2001;89:105–107.
- Suttner DM, Dennery PA. Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. FASEB J 1999;13:1800–1809.
- Du ZY, Hicks M, Winlaw D, Spratt P, Macdonald P. Ischemic preconditioning enhances donor lung preservation in the rat. J Heart Lung Transplant 1996;15:1258–1267.
- Friedrich I, Spillner J, Lu EX, Bartling B, Barnscheid M, Sablotzki A, Schade U, Reidemeister JC, Silber RE, Gunther A, et al. Ischemic pre-conditioning of 5 minutes but not of 10 minutes improves lung function after warm ischemia in a canine model. J Heart Lung Transplant 2001;20:985–995.
- Gasparri RI, Jannis NC, Flameng WJ, Lerut TE, Van Raemdonck DE. Ischemic preconditioning enhances donor lung preservation in the rabbit. Eur J Cardiothorac Surg 1999;16:639–646.
- Li G, Chen S, Lou W, Lu E. Protective effects of ischemic preconditioning on donor lung in canine lung transplantation. Chest 1998;113:1356–1359.
- Javadpour M, Kelly CJ, Chen G, Stokes K, Leahy A, Bouchier-Hayes DJ. Thermotolerance induces heat shock protein 72 expression and protects against ischaemia-reperfusion-induced lung injury. Br J Surg 1998;85:943–946.
- Hiratsuka M, Yano M, Mora BN, Nagahiro I, Cooper JD, Patterson GA. Heat shock pretreatment protects pulmonary isografts from subsequent ischemia-reperfusion injury. J Heart Lung Transplant 1998;17:1238–1246.
- Hirata T, Fukuse T, Ishikawa S, Hanaoka S, Chen Q, Shoji T, Wada H. "Chemical preconditioning" by 3-nitropropionate reduces ischemia-reperfusion injury in cardiac-arrested rat lungs. Transplantation 2001;71:352–359.
- Schutte H, Witzenrath M, Mayer K, Rosseau S, Seeger W, Grimminger F. Short-term "preconditioning" with inhaled nitric oxide protects rabbit lungs against ischemia-reperfusion injury. Transplantation 2001;2:1363–1370.
- Waddell TK, Hirai T, Piovesan J, Oka T, Puskas JD, Patterson GA, Slutsky AS. The effect of heat shock on immediate post-preservation lung function. Clin Invest Med 1994;17:405–413.
- Benjamin IJ, McMillan DR. Stress (heat shock) proteins: molecular chaperones in cardiovascular biology and disease. Circ Res 1998;83:117–132.
- Maulik N, Engelman RM, Wei Z, Liu X, Rousou JA, Flack JE, Deaton DW, Das DK. Drug-induced heat-shock preconditioning improves postischemic ventricular recovery after cardiopulmonary bypass. Circulation 1995;92:II381–II388.
- Xuan YT, Tang XL, Banerjee S, Takano H, Li RC, Han H, Qiu Y, Li JJ, Bolli R. Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res 1999;84:1095–1109.
- Fukuse T, Hirata T, Omasa M, Wada H. Effect of adenosine triphosphate-sensitive potassium channel openers on lung preservation. Am J Respir Crit Care Med 2002;165:1511–1515.
- Neely CF, Keith IM. A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung. Am J Physiol 1995;268:L1036–L1046.
- Clavien PA, Yadav S, Sindram D, Bentley RC. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg 2000;232:155–162.
- Wu ZK, Tarkka MR, Eloranta J, Pehkonen E, Kaukinen L, EHonkonen EL, Kaukinen S. Effect of ischemic preconditioning on myocardial protection in coronary artery bypass graft patients: can the free radicals act as a trigger for ischemic preconditioning? Chest 2001;119:1061–1068.
- Cassivi SD, Liu M, Boehler A, Pierre A, Tanswell AK, O'Brodovich H, Mullen JB, Slutsky AS, Keshavjee SH. Transplant immunosuppression increases and prolongs transgene expression following adenoviral-mediated transfection of rat lungs. J Heart Lung Transplant 2000;19:984–994.
- Cassivi SD, Liu M, Boehler A, Tanswell AK, Slutsky AS, Keshavjee S, Todd TRJ. Transgene expression after adenovirus-mediated retransfection of rat lungs is increased and prolonged by transplant immunosuppression. J Thorac Cardiovasc Surg 1999;117:1–7.
- Cassivi SD, Cardella JA, Fischer S, Liu M, Slutsky AS, Keshavjee S. Transtracheal gene transfection of donor lungs prior to organ procurement increases transgene levels at reperfusion and following transplantation. J Heart Lung Transplant 1999;18:1181–1188.
- Yano M, Hiratsuka M, Mora BN, Scheule RK, Patterson GA. Transfection of pulmonary artery segments in lung isografts during storage. Ann Thorac Surg 1999;68:1810–1814.
- Yano M, Hiratsuka M, Nagahiro I, Mora BN, Scheule RK, Patterson GA. Ex vivo transfection of pulmonary artery segments in lung isografts. Ann Thorac Surg 1999;68:1805–1809.
- Suda T, D'Ovidio F, Daddi N, Ritter JH, Mohanakumar T, Patterson GA. Recipient intramuscular gene transfer of active transforming growth factor-beta1 attenuates acute lung rejection. Ann Thorac Surg 2001;71:1651–1656.
- Itano H, Zhang W, Ritter JH, McCarthy TJ, Mohanakumar T, Patterson GA. Adenovirus-mediated gene transfer of human interleukin 10 ameliorates reperfusion injury of rat lung isografts. J Thorac Cardiovasc Surg 2000;120:947–956.
- D'Ovidio F, Daddi N, Suda T, Grapperhaus K, Patterson GA. Efficient naked plasmid cotransfection of lung grafts by extended lung/plasmid exposure time. Ann Thorac Surg 2001;71:1817–1823.
- Fischer S, Liu M, Maclean AA, de Perrot M, Ho M, Cardella JA, Zhang XM, Bai XH, Suga M, Imai Y, et al. In vivo transtracheal adenovirus-mediated transfer of human interleukin-10 gene to donor lungs ameliorates ischemia-reperfusion injury and improves early posttransplant graft function in the rat. Hum Gene Ther 2001;12:1513–1526.
- Yano M, Mora BN, Ritter JM, Scheule RK, Yew NS, Mohanakumar T, Patterson GA. Ex vivo transfection of transforming growth factor-beta1 gene to pulmonary artery segments in lung grafts. J Thorac Cardiovasc Surg 1999;117:705–713.
- Chapelier A, Danel C, Mazmanian M, Bacha EA, Sellak H, Gilbert MA, Herve P, Lemarchand P. Gene therapy in lung transplantation: feasibility of ex vivo adenovirus-mediated gene transfer to the graft. Hum Gene Ther 1996;7:1837–1845.
- Tagawa T, Suda T, Daddi N, Kozower BD, Kanaan SA, Mohanakumar T, Patterson GA. Low-dose endobronchial gene transfer to ameliorate lung graft ischemia-reperfusion injury. J Thorac Cardiovasc Surg 2002;123:795–802.
- Eppinger MJ, Ward PA, Bolling SF, Deeb GM. Regulatory effects of interleukin-10 on lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 1996;112:1301–1305.
- Martins SC, de Perrot M, Imai Y, Chaparro A, Sakiyama S, Quadri M, Segall L, Waddell TK, Liu M, Keshavjee S. Endoscopic delivery of adenoviral-mediated human interleukin-10 gene to the donor improves post transplant lung function in a large animal model . J Heart Lung Transplant 2002;21:212.
作者：
Marc de Perrot, Mingyao Liu, Thomas K. Waddell and 2007-5-14