In vivo and in vitro effects of SAR 943, a rapamycin analogue, on airway inflammation and remodeling.
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.
Fujitani
Yasushi
Y
Novartis Respiratory Research Centre, Horsham, United Kingdom.
Trifilieff
Alexandre
A
D000281:Administration, Intranasal; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D019819:Budesonide / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D011014:Pneumonia / Q000188:drug therapy* / Q000503:physiopathology; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000494:pharmacology*; D018709:Statistics, Nonparametric
D019819:Budesonide; D010047:Ovalbumin; D020123:Sirolimus