Novartis Respiratory Research Centre, Horsham, United Kingdom
No current therapy is considered to be satisfactory for severe
asthma, and alternative approaches are still required for what
is a major unmet medical need. In this study, we compared the
effect of a rapamycin derivative, SAR 943, with budesonide,
using a murine model of lung inflammation and remodeling. Allergen
challenge of ovalbumin-sensitized BALB/c mice induced an increase
in the levels of interleukin-5 and interleukin-4; numbers of
eosinophil, neutrophil, and lymphocyte; cellular fibronectin;
lung epithelial cell proliferation and mucus hypersecretory
phenotype; as well as hyperreactivity to methacholine. Both
SAR 943 and budesonide, when given intranasally 1 hour before
and 24 hours after the aerosol challenge, inhibited all of these
parameters with a similar potency (effective dose 50% of 1 mg/kg).
In primary cultured smooth muscle cells from human airways,
SAR 943 dose dependently inhibited epidermal growth factor–induced
proliferation but did not affect the basal cell proliferation.
Neither the basal nor stimulated proliferation of a human bronchial
epithelial cell line (16HBE14o-) was affected by SAR 943. In
conclusion, SAR 943 is as effective as budesonide in inhibiting
both lung inflammation and remodeling in a murine model of asthma.
Hence, this class of compound could offer beneficial effects
in patients with severe asthma.
Key Words: mice • inflammation • remodeling • immunosuppressant
An unbalanced immune response and ensuing inflammation are acknowledged
to be major contributors to the initiation and chronicity of
the asthmatic process, as they are the basis of a cascade of
cellular and mediator interactions resulting in a pulmonary
inflammatory cell infiltrate (
1). In addition to the inflammatory
component, structural changes in the architecture of the airways
have been reported. These changes include basement membrane
thickening caused by collagen and fibronectin deposition, fibroblast
proliferation, airway smooth muscle thickening as a result of
both smooth muscle cell hyperplasia and hypertrophy, and excessive
production of mucus glycoproteins (
2). These modifications,
collectively termed lung remodeling, lead to the thickening
of the airway wall, which in turn could explain the chronic
irreversible hyperresponsiveness that has been observed in this
disease (
3). Although inhaled corticosteroids and ß
2 adrenergic agonists remain the drugs of choice for the majority
in the treatment of chronic asthma, there remains a small group
of patients who are characterized by ongoing symptoms and who
experience frequent exacerbation despite the use of existing
therapies. These patients, referred to as severe or difficult-to-treat
subjects with asthma, are often treated with high doses of inhaled
corticosteroids and/or oral corticosteroids and are at risk
of developing unwanted side effects (
4). Therefore, the identification
of a novel therapy for these patients is urgently needed. One
approach to treat these patients has been to use T cell immunomodulators
such as cyclosporin A, a powerful immunosuppressant agent that
is used mainly for the prevention of rejection during organ
transplantation. In human studies, cyclosporin A has been shown
to be a corticosteroid-sparing agent in severe asthma. However,
this was associated with side effects such as an increase in
diastolic blood pressure and a decrease in renal function (
5,
6). Thus, the current therapy for severe and very severe asthma
presently available is less than satisfactory, and an alternative
approach is regarded as a major medical need.
Rapamycin, an immunosuppressive macrolide, has attracted interest in recent years because of its potential in the treatment of various immunologic disorders, including asthma (7). In addition to its immunosuppressant properties, rapamycin also inhibits smooth muscle cell proliferation (8, 9), an important feature of remodeling. Unfortunately, this natural product exhibits unfavorable physicochemical properties. As a consequence, its formulation and administration in an appropriate therapeutic form have been proven to be rather difficult. SAR 943 (32-Deoxorapamycin), a novel rapamycin derivative with immunosuppressive properties, has been identified out of a series of rapamycin derivatives with chemical modifications designed to increase the chemical stability in galenical formulation (10). In view of its biologic properties, it is speculated that SAR 943 has a dual target in asthma, as it has the potential to work as an antiinflammatory and antiremodeling drug. To test this hypothesis, we have studied the effect of SAR 943 in a murine model of allergen-driven lung inflammation that presents some aspects of the remodeling seen in human asthma (11) and compared its potency with budesonide. Data illustrating the antiproliferative effect of SAR 943 on human epithelial and smooth muscle cells were also studied in vitro and are presented.
Animals and Experimental DesignThe studies reported herein conformed to the UK Animals (scientific
procedures) Act of 1986. All of the procedures used in this
article have been previously described by this laboratory (
11,
12). In brief, female BALB/c mice were immunized on Days 0 and
14 and were exposed to a single aerosol of ovalbumin on Day
21. On Day 20, ALZET minipumps filled with 5-bromo-2'-deoxyuridine
(10 mg/ml) were implanted subcutaneously in the scapular region
of some of the mice. SAR 943 and budesonide were dissolved in
dimethyl sulfoxide and then diluted with phosphate-buffered
saline (PBS) (final concentration of dimethyl sulfoxide of 2%).
Animals were dosed intranasally under halothane/oxygen/nitrous
oxide anesthesia, with either test compound or vehicle (50 µl)
1 hour before and 24 hours after the aerosol challenge. On Day
22, airway hyperreactivity to aerosolized methacholine (0.1
M) was measured using barometric plesthysmography. Cytokine
levels were determined (interleukin [IL]-4, IL-5, and interferon-
作者：
Yasushi Fujitani and Alexandre Trifilieff 2007-5-14