INHIBITION BY RAPAMYCIN OF LEUKOCYTE MIGRATION AND BRONCHIAL HYPERREACTIVITY INDUCED BY INJECTION OF SEPHADEX BEADS TO GUINEA-PIGS

1 The effect of rapamycin (0.001 to 5 mg kg-1) on the increased leukoc yte counts in bronchoalveolar lavage (BAL) fluid and hyperreactivity o f isolated bronchial strips to histamine and acetylcholine (ACh) was s tudied following the intravenous injection of Sephadex beads to guinea -pigs. 2 The intramuscular (i.m.) injection of rapamycin (0.012 to 5 m g kg-1) dose-dependently inhibited the increase in leukocyte counts in BAL fluid. Rapamycin (5 mg kg-1) reduced the numbers of eosinophils n eutrophils, macrophages and lymphocytes in BAL fluid by 64, 55, 19 and 50% respectively. In addition, rapamycin (0.0 1 2 to 5 mg kg-1) signi ficantly inhibited the Sephadex-induced hyperreactivity of bronchial t issue to both histamine and ACh. 3 At a dose of 0.001 mg kg-1, rapamyc in did not significantly reduce leukocyte infiltration or bronchial hy perreactivity. 4 Cyclosporin (5 mg kg-1) significantly reduced both ly mphocyte and eosinophil numbers in BAL fluid of Sephadex-injected guin ea-pigs whereas dexamethasone (I mg kg-1) significantly reduced lympho cyte numbers. Neither drug affected the bronchial hyperreactivity to h istamine and ACh. 5 It is concluded that the new immunosuppressive dru g, rapamycin, is a potent inhibitor of leukocyte migration and bronchi al hyperreactivity observed following the intravenous injection of Sep hadex beads to guinea-pigs. Rapamycin also appears to be more effectiv e than cyclosporin or dexamethasone in reducing leukocyte counts and b ronchial hyperreactivity in this model. 6 Our results suggest that inf lammatory mechanisms which are inhibited by rapamycin may be important in the induction of Sephadex-induced hyperreactivity.