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  Unopposed Cathepsin G, Neutrophil Elastase, and Proteinase 3 Cause Severe Lung Damage and Emphysema

Guyot, N., Wartelle, J., Malleret, L., Todorov, A. A., Devouassoux, G., Pacheco, Y., et al. (2014). Unopposed Cathepsin G, Neutrophil Elastase, and Proteinase 3 Cause Severe Lung Damage and Emphysema. AMERICAN JOURNAL OF PATHOLOGY, 184(8), 2197-2210. doi:10.1016/j.ajpath.2014.04.015.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0023-C3B6-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0023-C3B7-8
Genre: Journal Article

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 Creators:
Guyot, Nicolas1, Author
Wartelle, Julien1, Author
Malleret, Laurette1, Author
Todorov, Alexandre A.1, Author
Devouassoux, Gilles1, Author
Pacheco, Yves1, Author
Jenne, Dieter E.2, Author              
Belaaouaj, Azzaq1, Author
Affiliations:
1external, ou_persistent22              
2Research Group: Enzymes and Inhibitors in Chronic Lung Disease / Jenne, MPI of Neurobiology, Max Planck Society, ou_1950284              

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Free keywords: OBSTRUCTIVE PULMONARY-DISEASE; SMOKE-INDUCED EMPHYSEMA; PSEUDOMONAS-AERUGINOSA; LEUKOCYTE ELASTASE; SERINE PROTEASES; HOST-DEFENSE; NONOXIDATIVE MECHANISM; DEFICIENT MICE; GELATINASE B; INFLAMMATION
 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 alpha(1)-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.

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Language(s): eng - English
 Dates: 2014-08
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Degree: -

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Title: AMERICAN JOURNAL OF PATHOLOGY
Source Genre: Journal
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Publ. Info: 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA : ELSEVIER SCIENCE INC
Pages: - Volume / Issue: 184 (8) Sequence Number: - Start / End Page: 2197 - 2210 Identifier: ISSN: 0002-9440