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Selectin-dependent rolling and adhesion of leukocytes in nicotine-exposed microvessels of lung allografts

Division of Vascular Biology, La Jolla Institute for Molecular Medicine, San Diego, California 92121

Submitted 23 December 2002 ; accepted in final form 22 May 2003

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 skinfold 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 demonstrated that nicotine significantly enhanced rolling and adhesion of leukocytes within lung microvessels comprising arterioles and postcapillary 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 monoclonal antibodies (MAbs) against L-, E-, or P-selectin after exposure of lung allografts to nicotine resulted in variable but significant inhibition of nicotine-induced rolling, whereas 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 PD-98059, 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 1/2, which could be blocked by PD-98059. 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.

selectins; endothelium; leukocyte recruitment; pulmonary; adhesive interactions

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