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Am. J. Respir. Cell Mol. Biol., Volume 22, Number 2, February, 2000 244-252

Acute Cigarette Smoke-Induced Connective Tissue Breakdown Is Mediated by Neutrophils and Prevented by alpha 1-Antitrypsin

Rajwinder Dhami, Blake Gilks, Changshi Xie, Katalin Zay, Joanne L. Wright, and Andrew Churg

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

Recent studies have suggested that macrophage-derived metalloproteases are the critical mediators of cigarette smoke-induced emphysema, in contrast to earlier hypotheses that this process was mediated by neutrophil elastase. To determine whether smoke can acutely induce connective tissue breakdown in the lung and to examine the mediators of this process, we exposed C57-BL/6 mice to whole cigarette smoke and used high-performance liquid chromatography to examine lavage fluid levels of desmosine (DES), a marker of elastin breakdown, and hydroxyproline (HP), a marker of collagen breakdown. Smoke produced a dose-response increase in lavage neutrophils, DES, and HP, but not lavage macrophages (MACs). This effect was evident by 6 h after exposure to two cigarettes. Pretreatment with an antibody against polymorphonuclear leukocytes (PMNs) reduced lavage PMNs to undetectable levels after smoke exposure, did not affect MAC numbers, and prevented increases in lavage DES and HP. Intraperitoneal injection of a commercial human alpha 1-antitrypsin (alpha 1AT) 24 h before smoke exposure increased serum alpha 1AT levels approximately 3-fold and completely abolished smoke-induced connective tissue breakdown as well as the increase in lavage PMNs, again without affecting MAC numbers. We conclude that in this model cigarette smoke can acutely induce connective tissue breakdown and that this effect is mediated by neutrophil-derived serine proteases, most likely neutrophil elastase. Exogenous alpha 1AT is protective and appears to inhibit both matrix degradation and PMN influx, suggesting that alpha 1AT has anti-inflammatory as well as antiproteolytic effects in this system.




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