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Guyot, N.* ; Wartelle, J.* ; Malleret, L.* ; Todorov, A.A.* ; Devouassoux, G.* ; Pacheco, Y.* ; Jenne, D. ; Belaaouaj, A.*

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

Am. J. Pathol. 184, 985-995 (2014)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Obstructive Pulmonary-disease; Smoke-induced Emphysema; Pseudomonas-aeruginosa; Leukocyte Elastase; Serine Proteases; Host-defense; Nonoxidative Mechanism; Deficient Mice; Gelatinase B; Inflammation
ISSN (print) / ISBN 0002-9440
e-ISSN 1525-2191
Zeitschrift American Journal of Pathology, The
Quellenangaben Band: 184, Heft: 8, Seiten: 985-995 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Lung Health and Immunity (LHI)