Wood smoke-induced airway hyperreactivity in guinea pigs: Time course, androle of leukotrienes and hydroxyl radical

A prior airway exposure to wood smoke induces a tachykinin-dependant increa se in airway responsiveness to the subsequent smoke inhalation in guinea pi gs (Life Sci. 63: 1513, 1998). To further investigate the time course of, a nd the contribution of other chemical mediators to, this smoke-induced airw ay hyperresponsiveness (SIAHR), two smoke challenges teach 10 mi) separated by 30 min were delivered into the lungs of anesthetized guinea pigs by a r espirator. In the control animals, the SIAHR was evidenced by the bronchoco nstrictive response to the second smoke challenge (SM2) which was similar t o 5.2-fold greater than that to the first challenge (SM1). This SIAHR was a lleviated by shortening the elapsed time between SM1 and SM2 to 10 min or b y extending it to 60 min, and was abolished by extending it to 120 min. Thi s SIAHR was reduced by pretreatment with either MK-571 (a leukotriene D-4-r eceptor antagonist) or dimethylthiourea (a hydroxyl radical scavenger), but was not affected by pretreatment with either pyrilamine (a histamine H-1-r eceptor antagonist) or indomethacin (a cyclooxygenase inhibitor). The smoke -induced reduction in the neutral endopeptidase activity (a major enzyme fo r tachykinin degradation) measured in airway tissues excised 30 min post SM 1 was largely prevented by pretreatment with dimethylthiourea. However, thi s reduction was not seen in airway tissues excised 120 min post SM1. These results suggest that 1) the SIAHR to inhaled wood smoke has a rapid onset t ime following smoke inhalation and lasts for less than two hours, 2) leukot rienes and hydroxyl radical may play contributory roles in the development of this SIAHR, and 3) hydroxyl radical is the major factor responsible for the smoke-induced inactivation of airway neutral endopeptidase, which may p ossibly participate in the development of this SIAHR.