This article surveys elastinolytic proteinases in man, excluding enzymes of the pancreas and digestive tract. Special emphasis is placed on the elastase of polymorphonuclear neutrophils (PMN). The properties of this latter enzyme, its target molecules in plasma and connective tissues, and its endogenous regulators are briefly discussed. Persistent activity of the enzyme, even in the presence of its regulatory inhibitors, is explained. The chapter closes with a brief discussion of several pulmonary diseases in which elastase-mediated tissue injury is thought to play a role.

The elastase inhibitory capacity per mg of atproteinase inhibitor (aPI)

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Past studies have focused attention on the lysosomal proteinases of polymorphonuclear leukocytes (PMN) as mediators of vascular injury (1-6). A specific association between the hydrolases in these ceils and selected targets in vessel wails was suggested by Cochrane and Aiken, who showed that acid-cathepsins D and E extracted from rabbit PMN granules could digest vascular basement membrane in vitro (5). As pointed out by these same authors, acid-cathepsinmediated vessel damage presupposes significant lowering of local pH. It remains to be determined whether sufficient acidity can be maintained at the tissueblood interface to permit such reactions to occur in vivo.Recently, evidence has appeared of vascular damage by leukocyte proteinases with neutral pH optima. A neutral mucoproteinase has been detected in rabbit PMN granules (7), and neutral proteinases have been purified from Arthus edema fluid in this species (8). Human neutrophiles are also known to contain neutral proteolytic activity or "leukoprotease" (9-12). We recently reported that extracts of human PMN granules could degrade vascular basement membrane at physiological pH in vitro and in vivo (6). Indeed, a neutral collagenase has been found in human PMN granules (13) and may be responsible for the lysis of vascular basement membranes occurring at physiological pH.The present studies were undertaken to examine the neutral proteinases of human neutrophilic leukocytes for possible activity against elastin. This sialoprotein comprises the elastic lamina and supportive fibers present in the walls of arterial and major venous blood vessels. Such activity, if present, would help account for the development of arterial lesions in PMN-mediated arteritis.Our results show that the granules of human PMN contain neutral elastinolyric activity which can be separated from the collagenolytic activity present in these cells. The data also demonstrate that the properties of elastolysis

Three synthetic inhibitors of proteases (tosyl lysine chloromethyl ketone, tosyl phenylalanine chloromethyl ketone, and tosyl arginine methyl ester) inhibit the tumorigenesis initiated in mouse skin by 7,12-dimethylbenz(a)anthracene and promoted by croton oil or its active principle, phorbol ester. These protease inhibitors, when applied directly to mouse skin, inhibit some of the irritant effects of the tumor promoter and are not toxic.