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Published ahead of print on June 30, 2005, doi:10.1165/rcmb.2005-0203OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 33, pp. 387-393, 2005
© 2005 American Thoracic Society
DOI: 10.1165/rcmb.2005-0203OC

Transforming Growth Factor-{beta}1 Drives Airway Remodeling in Cigarette Smoke–Exposed Tracheal Explants

Rong D. Wang, Joanne L. Wright and Andrew Churg

Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Andrew Churg, M.D., Department of Pathology, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5 Canada. E-mail: achurg{at}interchange.ubc.ca

Small airway remodeling (SAR) is an important cause of airflow obstruction in cigarette smokers, but whether SAR represents a response to smoke-evoked inflammation or is directly mediated by smoke-induced growth factor production is disputed. To examine this process, we exposed rat tracheal explants, a model free of exogenous inflammatory cells, to cigarette smoke in vitro. Cigarette smoke caused release of active transforming growth factor (TGF)-{beta}1, and this was prevented by the oxidant scavenger tetramethythiourea. Nuclear immunostaining for phospho-Smad2, a TGF-{beta} downstream signaling molecule, was present in epithelial and interstitial cells within 1 h after exposure. Smoke caused upregulation of gene expression of connective tissue growth factor (CTGF), a mediator of TGF-{beta} fibrogenic effects, within 2 h, and upregulation of procollagen gene expression at 24 h; both changes could be prevented by the TGF-{beta} antagonist fetuin ({alpha}2-HS-glycoprotein). In a cell-free system, recombinant human TGF-{beta} latency-associated peptide was oxidized by cigarette smoke, and smoke released active TGF-{beta}1 from recombinant latent TGF-{beta}1 via an oxidant mechanism. These experiments suggest that SAR in cigarette smokers may be caused by direct, smoke-mediated, oxidant-driven induction of growth factor signaling in the airway wall, and that SAR does not necessarily require exogenous inflammatory cells.

Key Words: cigarette smoke • chronic obstructive pulmonary disease • connective tissue growth factor • oxidants • transforming growth factor-{beta}




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