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

摘要: Cigarette smoking is a major factor for the development of pulmonary emphysema because it induces abnormal inflammation and protease-rich local milieu that causes connective tissue breakdown lungs. As result its capacity to degrade lung high risk patients lacking α 1 -antitrypsin develop emphysema, much interest has focused on neutrophil elastase (NE). Two similar serine proteases (NSPs), cathepsin G proteinase 3, coexist with NE in humans mice, but their potential tissue-destructive role(s) remains unclear. Using gene-targeting approach, we observed contrast wild-type littermates, mice deficient all three NSPs were substantially protected against destruction after long-term exposure cigarette smoke. In exploring underlying basis disrupted air spaces, found active collectively caused more severe damage than did alone. Furthermore, NSP activities unleashed increased activity macrophage (matrix metalloproteinase-12) gelatinase B metalloproteinase-9). These in vivo data provide, first time, compelling evidence collateral involvement G, NE, 3 smoke–induced emphysema. They also reveal complex positive feed-forward loop whereby these induce destructive other proteases, thereby generating chronic pathogenic milieu.