Elastolysis by proteinase 3 and its inhibition by alpha(1)-proteinase inhibitor: a mechanism for the incomplete inhibition of ongoing elastolysis.
An excess of proteinase 3 (Pr3) is an assumed risk factor for elastin loss in chronic obstructive pulmonary disease. This study compared the degradation of [(14)C]elastin by Pr3 and its inhibition by alpha(1)-proteinase inhibitor (alpha(1)-PI) with the analogous reactions involving two other neutrophil serine proteases, human leukocyte elastase (HLE) and cathepsin G (CatG). The elastolytic rate catalyzed by Pr3 was estimated to be half of that of CatG and one-eighth of that of HLE. Evidence was obtained that indicated that absorption of Pr3 by the substrate was much less than that of HLE or CatG, and that the majority of absorbed Pr3 was highly mobile. These properties are consistent with the observation that elastolysis by Pr3 was almost completely and stoichiometrically inhibited by alpha(1)-PI even under conditions in which the protease had been preincubated with the substrate. In contrast, alpha(1)-PI in large molar excess was unable to inhibit completely ongoing elastolysis of the same substrate by HLE or CatG. An interfacial nonisotropic reaction mechanism has been proposed to address the incomplete inhibition of ongoing elastolysis. Pr3 was identified as being the most abundant neutrophil serine protease. However, two findings reported here, namely the low rate of elastolysis by Pr3 and the high efficacy of alpha(1)-PI against ongoing elastolysis by Pr3, imply that Pr3 might not necessarily be a major contributor to neutrophil-mediated elastin loss.
Ying
Qi-Long
QL
Department of Pathology, State University of New York at Stony Brook, Stony Brook, New York 11794-8691, USA. qying@path.som.sunysb.edu
Simon
Sanford R
SR
D000818:Animals; D002417:Cattle; D004549:Elastin / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D053146:Myeloblastin; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013379:Substrate Specificity; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D004549:Elastin; D012697:Serine Endopeptidases; D053146:Myeloblastin