Published ahead of print on September 4, 2003, doi:10.1164/rccm.200307-1006OC Am. J. Respir. Crit. Care Med., Volume 168, Number 10, November 2003, 1232-1236 A more recent version of this article appeared on November 15, 2003
Submitted on July 23, 2003 Cigarette smoke produces airway wall remodeling in rat tracheal explantsRong D Wang1,1 Pathology, University of British Columbia, Vancouver, BC, Canada * To whom correspondence should be addressed. E-mail: achurg{at}interchange.ubc.ca.
Small airway remodeling (small airways disease) is a common finding in cigarette smokers and is an important cause of airflow obstruction. Airway remodeling is usually attributed to the effects of cigarette smoke-induced inflammation in the airway wall, but little is actually known about its pathogenesis. We exposed rat tracheal explants to cigarette smoke and then maintained them in air organ culture. At 24 hours after smoke exposure, there was a dose-dependent increase in gene expression of procollagen and a significant increase in tissue hydroxyproline, a measure of collagen content. Greater increases in procollagen gene expression were found with repeated smoke exposures. Increased procollagen gene expression could be prevented with SN50, a selective inhibitor of nuclear factor (NF)- Key words: Cigarette smoke, airway remodeling, oxidants, epidermal growth factor-receptor, nuclear factor-kappa B
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B activation, and superoxide dismutase, catalase, and tetramethylthiourea, scavengers of active oxygen species. AG1478, an inhibitor of epidermal growth factor receptor (EGFR) signaling, also prevented increased procollagen gene expression, but PD98059 and SB203580, inhibitors of mitogen activated protein kinases, did not. These findings indicate that cigarette smoke can directly induce airway remodeling, specifically airway wall fibrosis, probably through active oxygen species-dependent transactivation of the epidermal growth factor receptor and subsequent NF-
