CYTOKINE MEDIATION OF OZONE-INDUCED PULMONARY ADAPTATION

Previous studies have shown that a single exposure of animals to ozone (O-3) can induce protection or adaptation to the acute injurious effe cts of a subsequent O-3 challenge. Although a number of mechanisms hav e been proposed to account for this response, none appear to be fully explanatory, We examined the role interleukin (IL)-6 may play in the i nduction of adaptation to O-3-induced pulmonary injury. A statisticall y significant 29-fold increase in bronchoalveolar lavage fluid IL-6 le vels was observed in rats exposed to 0.5 ppm O-3 during nighttime hour s when compared with daytime hours even though similar kinetics of inf lammation were induced by each exposure. Animals receiving an initial nighttime O-3 exposure showed a lesser degree of inflammation followin g a subsequent O-3 exposure when compared with animals which received an initial daytime exposure. Rats pretreated with IL-6 both intratrach eally and intraperitoneally and subsequently exposed to O-3 showed a l esser degree of cellular inflammation when compared with respective co ntrols. Pretreatment of rats with anti-IL-6-receptor antibodies (ra) p rior to the nighttime O-3 exposure completely abrogated the O-3-induce d cellular adaptive response without effecting the inflammatory respon se induced by the initial nighttime O-3 exposure. In fact, administrat ion of anti-IL-6ra augmented the neutrophil influx following the secon d O-3 exposure. Anti-IL-6ra treatment did not alter the pulmonary edem a adaptive response? suggesting that the O-3-induced cellular and edem a adaptive responses are regulated by different mechanisms. Our data i ndicate that mobilization of pulmonary antioxidants does not play a ro le in the IL-6-mediated early cellular adaptive response and suggest t hat IL-6 is an essential mediator of the O-3-induced cellular adaptive response.