REDUCTION OF SEPHADEX-INDUCED LUNG INFLAMMATION AND BRONCHIAL HYPERREACTIVITY BY RAPAMYCIN

Rapamycin is a macrolide antibiotic whose potent immunosuppressor acti vity was recently described in vivo and in vitro. The aim of the prese nt work was to determine if rapamycin could affect an established infl ammatory response. Conscious pathogen-free Dunkin-Hartley guinea pigs (300-400 g) were injected intravenously with Sephadex beads (G50, supe rfine, 10 to 40 mum, 24 mg/kg) to induce, lung inflammation and bronch ial hyperreactivity. Bronchoalveolar lavage (BAL) fluid was collected 2,12 and 24 h after Sephadex administration and the cells were counted . Bronchial tissue was used to construct dose-response (contraction, g ) curves to histamine and acetylcholine 24 h after the Sephadex inject ion, using a cascade system. Results are presented as area under the l og dose-response curves. Test animals were injected with rapamycin (5 mg/kg) or its vehicle by the intramuscular route either 2 or 12 h afte r Sephadex injection and BAL fluid collected 24 h after Sephadex admin istration. Rapamycin administration 2 h after Sephadex reduced eosinop hil and lymphocyte numbers in BAL by 52 and 55%, respectively, but not ex vivo bronchial hyperreactivity induced by Sephadex injection. Howe ver, rapamycin administration 12 h after Sephadex reduced BAL eosinoph il and lymphocyte numbers (55 and 62%, respectively) and bronchial hyp erreactivity. The increase in neutrophil numbers in BAL induced by Sep hadex injection was not modified by rapamycin. Since lymphocyte number s in BAL were significantly increased in Sephadex-treated animals at 1 2 h but not at 2 h after Sephadex injection, the present results sugge st that the inhibition of bronchial hyperreactivity by rapamycin may b e dependent on the presence of lymphocytes elicited into the airways b y Sephadex injection.