Mutual Interaction between Airway Inflammation and β-Adrenoceptor Function

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We first investigated the mechanism by which acute ozone exposure (3 ppm for 2 hours) induces cytokine-induced neutrophil chemoattractant (CINC), a rat homologue of human IL-8. After ozone exposure, CINC concentration in bronchoalveolar lavage fluid (BALF) markedly increased. This induction of CINC protein was significantly attenuated by pretreatment with a tetrapeptide interleukin (IL)-1 beta converting enzyme (ICE) inhibitor, suggesting a pivotal role of endogenous IL-1 beta in this model. (manuscript submitted)We then examined the change in beta-adrenoceptor function after acute ozone exposure. Trachea and lung tissues were excised 24-hour after ozone. Tracheal smooth muscle and lung tissue strips were mounted in organ baths and isometric tension was monitored. Compared with tissues taken from air-exposed animals, ozone exposure caused reduced relaxation response to isoproterenol. The dysfunction of beta-adrenoceptor was significantly blocked by the pretreatment of tissue strips with pertussis toxin, indicating the receptor uncoupling via an induction of inhibitory G protein (Gi). Because tissue response to forskolin was also reduced, airway inflammation induced by ozone appeared to cause change(s) in the downstream of adenylate cyclase. This finding is analogous to our previous data with exogenous IL-1 instillation. We therefore evaluated the effect of ICE inhibitor and confirmed that inhibition of endogenous IL-1 beta production indeed prevents ozone-induced beta-adrenoceptor dysfunction.We now moved to the evaluation of the effect of beta-adrenal stimulation on airway inflammation. Especially, we have concentrated on the effect of intracellular cyclic AMP accumulation on eosinophil apoptosis. We have already confirmed that in vitro incubation with isoproterenol inhibits apoptosis of eosinophils, recovered from mice sensitized and challenged to ovalbumin.