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Carbon Monoxide Inhibits Human Airway Smooth Muscle Cell Proliferation via Mitogen-Activated Protein Kinase Pathway

Division of Pulmonary, Allergy and Critical Care Medicine, and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Address correspondence to: Augustine M. K. Choi, M.D., Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, MUH628, 3459 5th Avenue, Pittsburgh, PA 15213. E-mail: choiam{at}msx.upmc.edu

The gaseous molecule carbon monoxide (CO) is elevated in the breath of individuals with asthma. The physiologic function of CO in asthma is poorly understood. Here we demonstrate that CO (250 ppm) markedly inhibits human airway smooth muscle cell (HASMC) proliferation, arresting cells at the G0/G1 phase. This CO-induced cell growth arrest of HASMC was associated with upregulation of p21 and downregulation of cyclin D1 expression. It is generally believed that the signaling pathway by which CO affects biologic processes is primarily mediated via the guanylyl cyclase/3',5'-Guanylate cyclic monophosphate (cGMP) pathway. To examine whether guanylyl cyclase/cGMP was involved in CO-induced growth arrest of HASMC, Rp-8-Br-cGMP, a selective inhibitor of cGMP-dependent protein kinase and ODQ, a selective inhibitor of soluble guanylate cyclase, were administered to HASMC in the presence of CO. Interestingly, CO-induced cell growth arrest was not reversed by these inhibitors. We next examined whether the extracellular signal-regulated kinase (ERK) 1/ERK2 mitogen-activated protein kinase (MAPK) signaling pathway may regulate the antiproliferative effect of CO. We first showed time-dependent activation of the various MAPKs in HASMC in response to serum, including phosphorylated ERK1/ERK2, p38, and JNK and then demonstrated that CO exerted negligible effect on activated p38 and JNK; however, ERK activation was significantly attenuated in the presence of CO. These data suggest that CO can inhibit HASMC proliferation via the ERK1/ERK2 MAPK pathway, independent of a guanylyl cyclase/cGMP independent pathway. CO may act as an important mediator of remodeling of human airways in asthma via its ability to regulate cell growth of airway smooth muscle cells.

Abbreviations: carbon monoxide, CO • 3',5'-guanylate cyclic monophosphate, cGMP • extracellular signal-regulated kinase, ERK • fetal bovine serum, FBS • human airway smooth muscle cell, HASMC • heme oxygenases, HO • mitogen-activated protein kinase, MAPK • phosphate-buffered saline, PBS • vascular smooth-muscle cells, VSMC

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