Role of tachykinins in ozone-induced airway hyperresponsiveness to cigarette smoke is guinea pigs

Acute exposure to ozone (O-3) induces airway hyperresponsiveness to various inhaled bronchoactive substances. Inhalation of cigarette smoke, a common inhaled irritant in humans, is known to evoke a transient bronchoconstrictive effect. To examine whether O-3 increases airway responsiveness to cigarette smoke, effects of smoke inhalation challenge on total pulmonary resistance (RL) and dynamic lung compliance (Cdyn) were compared before and after exposure to O-3 (1.5 ppm, 1 h) in anesthetized guinea pigs. Before O-3 exposure, inhalation of two breaths of cigarette smoke (7 ml) at a low concentration (33%) induced a mild and reproducible bronchoconstriction that slowly developed and reached its peak (Delta RL = 67 +/- 19%, Delta Cdyn = -29 +/- 6%) after a delay of >1 min. After exposure to O-3 the same cigarette smoke inhalation challenge evoked an intense bronchoconstriction that occurred more rapidly, reaching its peak (Delta RL = 620 +/- 224%, Delta Cdyn = -35 +/- 7%) within 20 s, and was sustained far >2 min. By contrast, sham exposure to room air did not alter the bronchomotor response to cigarette smoke challenge. Pretreatment with CP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhanced responses of RL and Cdyn to cigarette smoke challenge induced by O-3. These results show that O-3 exposure induces airway hyperresponsive ness to inhaled cigarette smoke and that the enhanced responses result primarily from the bronchoconstrictive effect of endogenous tachykinins.