Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice.
To address the role of neutrophil elastase in pulmonary emphysema, neutrophil elastase-deficient mice and wild-type littermate controls were exposed to long-term cigarette smoke. Compared to wild-type littermates, mice that were deficient in neutrophil elastase were significantly protected (59%) from the development of emphysema. Previously, we demonstrated complete protection from emphysema in the absence of macrophage elastase. Further analysis revealed several interactions between these two elastases. Each elastase inactivated the endogenous inhibitor of the other, with neutrophil elastase degrading tissue inhibitor of metalloproteinase-1, and macrophage elastase degrading alpha-1-antitrypsin. Cigarette smoke-induced recruitment of both neutrophils and monocytes was impaired in the absence of neutrophil elastase. Moreover, there was less macrophage elastase activity secondary to decreased macrophage accumulation in neutrophil elastase-deficient mice. This study demonstrates a direct role for neutrophil elastase in emphysema and highlights the interdependence of the proteinases and inflammatory cells that mediate lung destruction in response to cigarette smoke.
Shapiro
Steven D
SD
Department of Pulmonary and Critical Care, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. sshapiro@rics.bwh.harvard.edu
Goldstein
Nir M
NM
Houghton
A McGarry
AM
Kobayashi
Dale K
DK
Kelley
Diane
D
Belaaouaj
Abderazzaq
A
D000818:Animals; D019272:Leukocyte Elastase / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D020556:Neutrophil Infiltration; D010196:Pancreatic Elastase / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D012906:Smoke / Q000009:adverse effects*; D013997:Time Factors; D014026:Nicotiana
D012906:Smoke; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12