Mechanisms of cigarette smoke-induced COPD: insights from animal models

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 294; no. 4; pp. L612 - L631
• Main Authors: Churg, Andrew, Cosio, Manuel, Wright, Joanne L
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.04.2008
• Subjects: Animals; Antioxidants - pharmacology; Chronic obstructive pulmonary disease; Cigarettes; Disease Models, Animal; Emphysema - etiology; Humans; Hypertension, Pulmonary - etiology; Lung - drug effects; Lung - pathology; Lungs; Pulmonary Disease, Chronic Obstructive - etiology; Smoking - adverse effects; Tobacco smoke
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00390.2007

1 Department of Pathology, University of British Columbia, Vancouver, British Columbia; and 2 Respiratory Division, Royal Victoria Hospital, and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches. animals; emphysema; small airway remodeling; pulmonary hypertension; chronic obstructive pulmonary disease Address for reprint requests and other correspondence: A. Churg, Dept. of Pathology, Univ. of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5 (e-mail: achurg{at}interchange.ubc.ca )