Cigarette Smoke Causes Small Airway Remodeling by Direct Growth Factor Induction and Release

Abstract

Hogg: Bronchiolitis in COPD 49332. Ingram JL, Rice AB, Geisenhoffer K, Madtes DK, Bonner JC. and IL-1beta promote lung fibroblast growth through coordinated upregulation of PDGF-AA and PDGF-Ralpha. FASEB J 2004;18:1132-1134. Cigarette Smoke Causes Small Airway Remodeling by Direct Growth Factor Induction and ReleaseAndrew Churg, Rong D. Wang, and Joanne L. WrightDepartment of Pathology, University of British Columbia, Vancouver, British Columbia, CanadaSmall airway remodeling (SAR) is one of the anatomic causes of airflow obstruction in patients with chronic obstructive pulmonary disease. The pathogenesis of SAR is poorly understood, but there are two general theories: (1 ) SAR is caused by smokeinduced inflammatory cells that damage the airway and evoke a repair process and (2 ) SAR is caused by direct induction of growth factors by cigarette smoke. To investigate this process, we briefly exposed rat tracheal explants, a model system free of exogenous inflammatory cells, to whole cigarette smoke, and then maintained the explants in organ culture for varying periods. With explants cultured in air, smoke induced up-regulation of both transforming growth factor (TGF)-␤ 1 and procollagen gene expression at 24 h after initial exposure. Increased procollagen gene expression was prevented in a dose-response fashion by the TGF-␤ antagonist fetuin, indicating that TGF-␤ was driving fibrosis. Collected supernatant from explants exposed to smoke and cultured in fluid medium showed increased release of TGF-␤ 1, and this was abolished by the oxidant scavenger tetramethylthiourea. Gene expression of connective tissue growth factor (CTGF) was sharply increased 2 h after smoke exposure. Using pure recombinant proteins, smoke-conditioned medium oxidized TGF-␤ latency-associated peptide and also caused release of active TGF-␤ 1 from latent TGF-␤ 1 . We conclude that cigarette smoke directly induces release of preformed TGF-␤ 1 by oxidizing the latency-associated peptide in rat tracheal explants, and that release must be extremely rapid, since gene expression of CTGF, the downstream fibrogenic driver of TGF-␤ effects on collagen synthesis, is elevated very shortly after smoke exposure. Although tracheal explants are only an approximate model of small airways, these findings suggest that smoke-induced SAR may reflect direct induction of growth factor release and signaling and does not require smoke-evoked inflammatory cells. Conflict of Interest Statement :None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. We have reported previously that MARCKS protein is a key regulatory molecule controlling mucin secretion by airway epithelial cells in vitro and in vivo, and presented evidence supporting a mechanism whereby MARCKS regulates secretion by translocating from plasma membrane to cytoplasm, where it binds to membranes of intracellular mucin granules (1, 2). The actual mechanism whereby MARCKS is targeted to and attaches onto membranes of mucin granules ha...

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