Effects of cyclosporin A and a rapamycin derivative (SAR943) on chronic allergic inflammation in sensitized rats.
Immunomodulators such as cyclosporin A (CsA) and SAR943 (32-deoxorapamycin) inhibit single allergen-induced allergic inflammation such as eosinophilic and lymphocytic infiltration and mRNA expression for interleukin (IL)-4 and IL-5. We examined the effects of CsA and SAR943, administered orally, on asthmatic responses in a rat model of chronic allergic inflammation. Sensitized Brown-Norway (BN) rats were exposed to ovalbumin (OVA) aerosol every third day on six occasions. CsA (5 mg/kg/day), SAR943 (2.5 mg/kg/day) or vehicle (Neoral) was administered orally, once a day, from days 10 to 21 (a total of 12 doses). We measured eosinophilic and T-cell inflammation in the airways, proliferation of airway cells by incorporation of bromodeoxyuridine (BrdU) and bronchial responsiveness to acetylcholine. CsA had no effects, while SAR943 inhibited airway smooth muscle (ASM, P < 0.05) and epithelial cell (P < 0.01) BrdU incorporation, and the number of CD4+ T cells (P < 0.05), without effects on BHR. ASM thickness was not significantly increased following chronic allergen exposure. Therefore, CsA and SAR943 have no effect on chronic eosinophilic inflammation, while SAR943, but not CsA, had a small effect on the proliferation of ASM and epithelium.
Eynott
Paul R
PR
National Heart & Lung Institute, Imperial College of Science, Technology & Medicine, London, UK.
Salmon
Michael
M
Huang
Tung-Jung
TJ
Oates
Timothy
T
Nicklin
Paul L
PL
Chung
K Fan
KF
D000109:Acetylcholine; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001985:Bronchial Provocation Tests; D016572:Cyclosporine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008297:Male; D009130:Muscle, Smooth / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D012137:Respiratory System / Q000473:pathology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000473:pathology; D014665:Vasodilator Agents
D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D016572:Cyclosporine; C476498:SAR943; D000109:Acetylcholine; D020123:Sirolimus