Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases.
Chronic obstructive pulmonary disease (COPD) is a common lung disease with cigarette smoking as the major etiological factor, but only 15% of smokers develop COPD. Destruction of lung elastin observed in COPD is mediated by many enzymes, including cysteine, serine, and matrix metalloproteinases (MMP). The contribution of these enzymes to the lung elastolytic load, released from alveolar macrophages collected from nonsmokers, healthy smokers, and COPD patients, was examined by radiolabeled elastin as substrate in the presence of specific enzyme inhibitors. The activity of MMP was further examined by zymography and Western blotting. COPD macrophages degraded more elastin than either of the other groups. Elastolysis was greatest in the initial 24 h. Through the 72-h culture period, the contribution to elastolysis of serine elastases decreased, MMP increased, and cysteine elastases remained constant. The increased release of elastolytic enzymes in COPD subjects may explain why some smokers develop COPD. This difference may be due to unknown susceptibility factors. Serine proteases play a significant role; however, other enzymes, particularly the MMP, deserve further investigation.
Russell
Richard E K
RE
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London SW3 6LY, United Kingdom.
Thorley
Andrew
A
Culpitt
Sarah V
SV
Dodd
Sara
S
Donnelly
Louise E
LE
Demattos
Carmen
C
Fitzgerald
Mary
M
Barnes
Peter J
PJ
D000368:Aged; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004548:Elasticity; D005260:Female; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000276:immunology; D008297:Male; D053508:Matrix Metalloproteinase 12; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012907:Smoking / Q000276:immunology / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D007930:Leucine; C024974:E 64