Inactivation of Serine Proteinase Inhibitors (Serpins) in Human Plasma by Reactive Oxidants

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Abstract
Activated polymorphonuclear neutrophils (PMN) and macrophages generate oxidizing agents similar to or identical with N-chloroamines. Mimicking this oxidation in normal human plasma by usage of chloramine T (CT), we observed an oxidant concentration dependent inactivating effect on plasma .alpha.2-plasmin inhibitor (.alpha.2-PI), antithrombin III (AT III), and .alpha.1-proteinase inhibitor (.alpha.1-PI). 20-50 .mu.mol CT/ml plasma are necessary for almost complete inactivation of .alpha.2-PI and AT III-activity, i.e. about 2-5 times the dose necessary for inactivation of .alpha.1-PI which has already been classified as "oxidant sensitive". The inactivation of .alpha.1-PI, .alpha.2-PI and AT III in plasma by oxidants is the result of a specific oxidative damage since C1-inhibitor, serine proteinases and complexes of plasmin and .alpha.2-PI were chloramine resistant under the conditions used. According to our results, the amount of chloramines released by 1 .times. 106 activated PMN, namely ca. 10 nmol (see Weiss et al. Science 222 625-628, 1983) would be sufficient to destroy .alpha.1-PI and .alpha.2-PI activity of 1.5 and 0.4 .mu.l of human plasma, respectively. Consequently, activated leukocytes may be able to create a microenvironment in which elastase as well as plasma and thrombin can display their proteolytic activity unchecked by their regulator proteins. Oxidation may provide a general basis for altering enzyme/inhibitor balances.

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