Role of the tachykinin NK(1 )receptor in a murine model of cigarette smoke-induced pulmonary inflammation

BACKGROUND: The tachykinins, substance P and neurokinin A, present in sensory nerves and inflammatory cells such as macrophages and dendritic cells, are considered as pro-inflammatory agents. Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increased tachykinin levels are recovered from the airways of COPD patients. The aim of our study was to clarify the involvement of the tachykinin NK(1 )receptor, the preferential receptor for substance P, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model of COPD. METHODS: Tachykinin NK(1 )receptor knockout (NK(1)-R(-/-)) mice and their wild type controls (all in a mixed 129/sv-C57BL/6 background) were subjected to sub acute (4 weeks) or chronic (24 weeks) exposure to air or CS. 24 hours after the last exposure, pulmonary inflammation and development of emphysema were evaluated. RESULTS: Sub acute and chronic exposure to CS resulted in a substantial accumulation of inflammatory cells in the airways of both WT and NK(1)-R(-/- )mice. However, the CS-induced increase in macrophages and dendritic cells was significantly impaired in NK(1)-R(-/- )mice, compared to WT controls, and correlated with an attenuated release of MIP-3α/CCL20 and TGF-β1. Chronic exposure to CS resulted in development of pulmonary emphysema in WT mice. NK(1)-R(-/- )mice showed already enlarged airspaces upon air-exposure. Upon CS-exposure, the NK(1)-R(-/- )mice did not develop additional destruction of the lung parenchyma. Moreover, an impaired production of MMP-12 by alveolar macrophages upon CS-exposure was observed in these KO mice. In a pharmacological validation experiment using the NK(1 )receptor antagonist RP 67580, we confirmed the protective effect of absence of the NK(1 )receptor on CS-induced pulmonary inflammation. CONCLUSION: These data suggest that the tachykinin NK(1 )receptor is involved in the accumulation of macrophages and dendritic cells in the airways upon CS-exposure and in the development of smoking-induced emphysema. As both inflammation of the airways and parenchymal destruction are important characteristics of COPD, these findings may have implications in the future treatment of this devastating disease.