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Published ahead of print on June 30, 2005, doi:10.1165/rcmb.2005-0203OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 4, October 2005, 387-393

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Submitted on May 30, 2005
Revised on June 21, 2005

TGF{beta}1 Drives Airway Remodeling in Cigarette Smoke-Exposed Tracheal Explants

Rong D Wang1, Joanne L Wright1, and Andrew Churg1*

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

* To whom correspondence should be addressed. 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 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 hour after exposure. Smoke caused upregulation of gene expression of connective tissue growth factor (CTGF), a mediator of TGF{beta} fibrogenic effects, within 2 hours, and upregulation of procollagen gene expression at 24 hours; 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.




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