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In Vivo and In Vitro Effects of SAR 943, a Rapamycin Analogue, on Airway Inflammation and Remodeling

Novartis Respiratory Research Centre, Horsham, United Kingdom

Correspondence and requests for reprints should be addressed to Alexandre Trifilieff, Novartis Respiratory Research Centre, Wimblehurst Road, Horsham RH12 5AB, UK. E-mail: alexandre.trifilieff{at}pharma.novartis.com

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

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