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

A prior airway exposure to wood smoke induces a tachykinin-dependent increase in airway responsiveness to the subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998). To further investigate the time course of, and the contribution of other chemical mediators to, this smoke-induced airway hyperresponsiveness (SIAHR), two smoke challenges (each 10 ml) separated by 30 min were delivered into the lungs of anesthetized guinea pigs by a respirator. In the control animals, the SIAHR was evidenced by the bronchoconstrictive response to the second smoke challenge (SM2) which was approximately 5.2-fold greater than that to the first challenge (SM1). This SIAHR was alleviated by shortening the elapsed time between SM1 and SM2 to 10 min or by extending it to 60 min, and was abolished by extending it to 120 min. This SIAHR was reduced by pretreatment with either MK-571 (a leukotriene D4-receptor antagonist) or dimethylthiourea (a hydroxyl radical scavenger), but was not affected by pretreatment with either pyrilamine (a histamine H1-receptor antagonist) or indomethacin (a cyclooxygenase inhibitor). The smoke-induced reduction in the neutral endopeptidase activity (a major enzyme for tachykinin degradation) measured in airway tissues excised 30 min post SM1 was largely prevented by pretreatment with dimethylthiourea. However, this 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 time following smoke inhalation and lasts for less than two hours, 2) leukotrienes 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 possibly participate in the development of this SIAHR.