Proteases and emphysema.
OBJECTIVE
The protease-antiprotease theory of emphysema is widely accepted, but exactly which cells/proteases play a role continues to be a controversial subject.


RESULTS
Reports in humans show increased metalloproteinase activity in emphysema, but the exact role of metalloproteinases remains unclear. In laboratory animals, neutrophils turn out to be crucial, and neutrophil influx correlates well with measurements of matrix destruction. Neutrophil influx is linked to metalloproteinase activity, and in mice MMP12-induced release of tumor necrosis factor-alpha drives neutrophil infiltration. Serine elastase inhibitors, knockout of neutrophil elastase, and interference with tumor necrosis factor-alpha signaling all provide significant protection against smoke-induced emphysema, but metalloproteinase inhibitors may yield greater protection. In genetically modified mice, emphysema can be produced by overexpression of mediators such as tumor necrosis factor-alpha, interferon-gamma, or interleukin-13, and these models show evidence of metalloproteinase, cysteine protease, and serine protease attack with complicated relationships among these mediators. Collagen breakdown also appears to be important in the genesis of emphysema. Pro-apoptotic agents produce emphysema as well, possibly via an elastolytic pathway.


CONCLUSIONS
The idea that a single protease or a single type of inflammatory cell is responsible for human emphysema is unlikely to be true; rather, there are complex interactions among proteases, and between proteases and other mediators. The problem at this time is attempting to sort out the numerous candidate effector agents and to determine which of the animal models are relevant to human disease, since there may be considerable discrepancies in the types of proteases and their roles between laboratory animals and humans. There is now good evidence from animal models that antiproteolytic therapy can be of benefit in ameliorating cigarette smoke-induced emphysema.
Churg
Andrew
A
Department of Pathology, University of British Columbia, Vancouver, BC, Canada. achurg@interchange.ubc.ca
Wright
Joanne L
JL
D000818:Animals; D017209:Apoptosis; D017364:Collagenases / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D004646:Emphysema / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use
D015842:Serine Proteinase Inhibitors; D045726:Metalloproteases; D010447:Peptide Hydrolases; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases; D017364:Collagenases