title: Unopposed cathepsin G, neutrophil elastase, and proteinase 3 cause severe lung damage and emphysema.
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.
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, EA-4303, Reims, Inserm U-1111, Lyon-Sud, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guyot
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, EA-4303, Reims, Inserm U-1111, Lyon-Sud, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Wartelle
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, EA-4303, Reims, Inserm U-1111, Lyon-Sud, France.
authors.forename: Laurette
authors.initials: L
authors.lastname: Malleret
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, EA-4303, Reims, Inserm U-1111, Lyon-Sud, France.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Todorov
authors.affiliation: 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.
authors.forename: Gilles
authors.initials: G
authors.lastname: Devouassoux
authors.affiliation: 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.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pacheco
authors.affiliation: 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.
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, EA-4303, Reims, Inserm U-1111, Lyon-Sud, France. Electronic address: azzaq.belaaouaj@inserm.fr.
authors.forename: Azzaq
authors.initials: A
authors.lastname: Belaaouaj
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056649:Cathepsin G / Q000378:metabolism*; D004195:Disease Models, Animal; D019272:Leukocyte Elastase / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053146:Myeloblastin / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects*
chemical_list: D056649:Cathepsin G; D019272:Leukocyte Elastase; D053146:Myeloblastin