The interaction of circulating leukocytes with lung microvessels is a critical event in the recruitment of effector cells into the interstitial tissue during episodes of inflammation including smoking-induced chronic airway disease. In the present study, murine lung tissue transplanted into a dorsal skin-fold window chamber in nude mice was used as a model system to study nicotine-induced leukocyte trafficking in vivo. The revascularized lung microvessels were determined to be of pulmonary origin based on their ability to constrict in response to hypoxia. We demonstrate that nicotine significantly enhances rolling and adhesion of leukocytes within lung microvessels comprising of arterioles and post-capillary venules in a dose-dependent manner, but failed to induce leukocyte emigration. Nicotine-induced rolling and adhesion was significantly higher in venules than in arterioles. Treatment of mice with mAbs against L-, E- or P-selectin after exposure of lung allografts to nicotine resulted in variable but significant inhibition of nicotine-induced rolling, while nicotine-induced subsequent adhesion was inhibited by mAbs against L- and P-selectin, but not E-selectin. Exposure of lung allografts to nicotine along with PD98059, a mitogen-activated protein kinase (MAPK) specific inhibitor, resulted in significant inhibition of nicotine-induced rolling and adhesion. In vitro, exposure of murine lung endothelial cells to nicotine resulted in increased phosphorylation of mitogen activated/extracellular signal-regulated protein kinase (ERK 1/2), which could be blocked by PD98059. Overall, these results suggest that nicotine-induced inflammation in the airways could potentially be due to MAPK-mediated, selectin-dependent leukocyte-endothelial cell interactions in the lung microcirculation.