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Am J Pathol. 2014 Aug;184(8):2197-210. doi: 10.1016/j.ajpath.2014.04.015. Epub 2014 Jun 12.

Unopposed cathepsin G, neutrophil elastase, and proteinase 3 cause severe lung damage and emphysema.

Author information

1
Inflammation and Immunity of the Respiratory Epithelium Group, EA-4303, Reims, Inserm U-1111, Lyon-Sud, France.
2
Inflammation and Immunity of the Respiratory Epithelium Group, EA-4303, Reims, Inserm U-1111, Lyon-Sud, France; CHU Croix-Rousse, Planegg-Martinsried and Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig Maximilians University and Helmholtz-Zentrum München, Munich, Germany.
3
CHU-Lyon-Sud, Planegg-Martinsried and Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig Maximilians University and Helmholtz-Zentrum München, Munich, Germany.
4
Max-Planck-Institute of Neurobiology, Planegg-Martinsried and Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig Maximilians University and Helmholtz-Zentrum München, Munich, Germany.
5
Inflammation and Immunity of the Respiratory Epithelium Group, EA-4303, Reims, Inserm U-1111, Lyon-Sud, France. Electronic address: azzaq.belaaouaj@inserm.fr.

Abstract

Cigarette smoking is a major factor for the development of pulmonary emphysema because it induces abnormal inflammation and a protease-rich local milieu that causes connective tissue breakdown of the lungs. As a result of its capacity to degrade lung tissue and the high risk of patients lacking α1-antitrypsin to develop emphysema, much interest has focused on neutrophil elastase (NE). Two similar neutrophil serine proteases (NSPs), cathepsin G and proteinase 3, coexist with NE in humans and mice, but their potential tissue-destructive role(s) remains unclear. Using a gene-targeting approach, we observed that in contrast to their wild-type littermates, mice deficient in all three NSPs were substantially protected against lung tissue destruction after long-term exposure to cigarette smoke. In exploring the underlying basis for disrupted wild-type lung air spaces, we found that active NSPs collectively caused more severe lung damage than did NE alone. Furthermore, NSP activities unleashed increased activity of the tissue-destructive proteases macrophage elastase (matrix metalloproteinase-12) and gelatinase B (matrix metalloproteinase-9). These in vivo data provide, for the first time, compelling evidence of the collateral involvement of cathepsin G, NE, and proteinase 3 in cigarette smoke-induced tissue damage and emphysema. They also reveal a complex positive feed-forward loop whereby these NSPs induce the destructive potential of other proteases, thereby generating a chronic and pathogenic protease-rich milieu.

PMID:
24929239
DOI:
10.1016/j.ajpath.2014.04.015
[Indexed for MEDLINE]

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