Aprotinin but Not Tranexamic Acid Inhibits Cytokine-Induced Inducible Nitric Oxide Synthase Expression

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Abstract
Cell expression of inducible nitric oxide synthase (iNOS) is increased by cytokines, which results in high endogenous concentrations of nitric oxide (NO) and has been implicated in organ injury, including myocardial reperfusion injury. Serine protease inhibitors reduce cytokine-induced iNOS expression. The protease inhibitors aprotinin and tranexamic acid, which are used to reduce blood loss after cardiac surgery, were evaluated in vitro on cytokine-induced iNOS expression and the resulting NO production to demonstrate the relative antiinflammatory effects of each drug. A murine bronchial epithelial cell line (LA-4) was stimulated with cytomix (tumor necrosis factor alpha, interleukin 1beta, and gamma-interferon) with or without aprotinin, tranexamic acid, or N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK; a protease inhibitor). The resultant iNOS expression was measured by using Northern blot analysis and cell supernatant nitrite concentrations (in aqueous media, NO is oxidized primarily to nitrite, NO2-) by chemiluminescence. Nitrite concentrations in the supernatant were significantly increased by cytomix, not affected by any concentration of tranexamic acid, but significantly (P < 0.05) reduced by aprotinin and TLCK. Consistent with the nitrite reduction, aprotinin significantly (P < 0.05) reduced cytokine-induced iNOS expression, while tranexamic acid had no effect. Aprotinin but not tranexamic acid reduces endogenous cytokine-induced NO production by inhibiting iNOS expression. Since increased endogenous NO concentrations secondary to iNOS activation have been implicated in organ injury, aprotinin may have clinical benefits when compared with tranexamic acid.