Matrix metalloproteinases: a role in emphysema?

The combined observations that (1) an inherited deficiency activity was found to be most strongly related to smoking, confirming previous studies. Interestingly, there was no of the major serum neutrophil elastase inhibitor, a1-proquantitative relationship between the enzyme levels, loss teinase inhibitor (a1-PI; a1-antitrypsin) predisposes to deof lung function, or degree of emphysema. Since their velopment of emphysema and (2) intratracheal instillation study suggests that these are largely neutrophil-derived of elastinolytic enzymes into rodents causes emphysema enzymes, these findings may simply reflect non-specific led to the elastase/anti-elastase imbalance hypothesis for neutrophil degranulation. The absence of NE in the nonthe development of the disease. This suggests that increased smokers or ex-smokers with emphysema (six of 10 were neutrophil influx and release of neutrophil elastase (NE) non-smokers), in whom lung function should stabilise, causes the tissue destruction and loss of elastic tissue suggests that NE is a significant contributory factor in the integrity that characterises emphysema. However, alprogression of emphysema. It would be interesting to know though NE is probably the pathological agent in a1-PI whether BAL fluid levels of collagenase are increased in deficiency, most of those with emphysema are smokers early emphysema, and also whether it might be active and with normal levels of a1-PI. Cigarette smoke inactivates atherefore cause tissue damage, rather than inactive, or PI in vitro and may induce environmental pulmonary a1raised in the face of tissue repair/remodelling. PI deficiency in vivo, but the evidence for this is conflicting. Why are neutrophil-derived proteases prevalent, even in Increased levels of neutrophils and extracellular NE are the face of a macrophage:neutrophil ratio of 45:1. What found in the bronchoalveolar lavage (BAL) fluid of happens to macrophage-derived proteases? Are they resmokers, but again the evidence that this is related to leased interstitially, rapidly removed from the site of action, interstitial tissue damage is unclear. Although some have and therefore overlooked? Are they important? Recent demonstrated a direct link between interstitial NE and observations by Shapiro and colleagues suggest that macrodegree of disease, others have not. 6 There is no definitive phage metalloelastase and gelatinase B expression are sigevidence that NE is directly related to emphysema in nificantly upregulated in the lungs of smokers. smokers. Unfortunately, emphysema is usually studied at an adThe search is on for alternative candidates. A protease vanced stage. Interstitial damage and tissue of interest has with elastinolytic activity of neutrophil or macrophage already disappeared and analysis of BAL fluid can only origin would be a strong contender. Neutrophils store the indicate what processes might be occurring interstitially. serine proteinases, NE, cathepsin G and proteinase 3, and Nevertheless, as the authors suggest, a combination of a metalloproteinase, gelatinase B, which is released in its neutrophil (and macrophage) proteases may represent the active form. 8 Macrophages also produce gelatinase B, and most pathological scenario in the development of emother metalloproteinases, macrophage metalloelastase and physema. stromelysin, but they require activation. Macrophages