Airway hyperresponsiveness induced by chronic exposure to cigarette smoke in guinea pigs: role of tachykinins

Abstract

This study was carried out to determine whether tachykinins released from lung C-fiber afferents play a part in the bronchial hyperreactivity induced in guinea pigs by chronic exposure to cigarette smoke (CS). Two matching groups of young guinea pigs were exposed to either mainstream CS (CS group) or air (control group) for 20 min twice daily for 14–17 days. There was no difference in the baseline total pulmonary resistance (Rl) between the two groups, but the baseline dynamic lung compliance was reduced (∼19%) in CS animals. The responses of Rl to intravenous injections of ACh, neurokinin (NK) A, and capsaicin were all markedly increased in CS animals; for example, ACh at the same dose of 5.06 μg/kg increased Rl by 207% in the control group and by 697% ( n = 8; P < 0.001) in the CS group. The increased responsiveness was accompanied by significant increases in the numbers of neutrophils, eosinophils, and macrophages in the bronchoalveolar lavage fluid in CS animals. Pretreatment with SR-48968 and CP-99994, antagonists of NK1and NK2 receptors, respectively, did not alter the response of Rlto ACh in control animals, but it abolished the elevated bronchoconstrictive response in the CS animals. Furthermore, the immunoreactivities of substance P and calcitonin gene-related peptide in the bronchoalveolar lavage fluid collected after capsaicin challenge were significantly increased in CS animals. These results show that chronic exposure to CS induced airway mucosal inflammation accompanied by bronchial hyperreactivity in guinea pigs and that the tachykininergic mechanism plays an important role in this augmented responsiveness.