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  • Title: Antiproteinases protect cultured lung endothelial cells from endotoxin injury.
    Author: Tumen J, Meyrick B, Berry L, Brigham KL.
    Journal: J Appl Physiol (1985); 1988 Aug; 65(2):835-43. PubMed ID: 2844719.
    Abstract:
    To determine whether the effects of endotoxin on cultured lung endothelium involve proteolytic mechanisms, we incubated bovine pulmonary arterial endothelial cells with endotoxin in medium 199 + 10% fetal bovine serum (FBS) in the presence and absence of several proteinase inhibitors. Three chloromethyl ketone (CK) derivatives [N-tosyl-L-lysine (CK)-(TLCK), N-tosyl-L-phenylalanine CK(TPCK), methoxysuccinyl-Ala-Ala-Pro-Val CK(SPCK)] and a single synthetic proteinase substrate [N-alpha-p-tosyl-L-arginine methyl ester hydrochloride (TAME)] attenuated endotoxin-induced cytotoxicity (lactate dehydrogenase release) and prostacyclin production in a dose-related fashion. The most effective inhibitors of endotoxin-induced cytotoxicity were TLCK and TPCK. TLCK and TAME most effectively attenuated endotoxin-stimulated prostacyclin production. Two chemically unrelated substances, soybean trypsin inhibitor and alpha 1 proteinase inhibitor also attenuated the endotoxin response. In the absence of FBS or in the presence of 10% heat-inactivated FBS, antiproteases attenuated endotoxin-induced prostacyclin production but had less effect on cytotoxicity than with 10% FBS. We also measured the capacity of the CK inhibitors to scavenge superoxide radicals generated in a cell-free xanthine/xanthine oxidase system by measuring inhibition of cytochrome c reduction. Percent scavenging of superoxide by these inhibitors was as follows: TLCK, 62.7 +/- 5.8 (SE); TPCK, 83.9 +/- 7.7; TAME, 24.5 +/- 6.4; SPCK, 0. We conclude that certain proteinase inhibitors attenuate endotoxin-induced endothelial cytotoxicity and prostacyclin production and that direct scavenging of superoxide radicals fails to explain the protective effects of proteinase inhibition. We speculate that the effects of endotoxin on lung endothelium may involve proteolytic mechanisms even in the absence of neutrophils.
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