User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse




Journal Article

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


Jenne,  Dieter E.
Research Group: Enzymes and Inhibitors in Chronic Lung Disease / Jenne, MPI of Neurobiology, Max Planck Society;

External Ressource
No external resources are shared
Fulltext (public)
There are no public fulltexts stored in PuRe
Supplementary Material (public)
There is no public supplementary material available

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.

Cite as: http://hdl.handle.net/11858/00-001M-0000-0023-C3B6-A
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.