M. Yuksel, K. Okajima, M. Uchiba
Apr 1, 2003
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Journal
Journal of Pharmacology and Experimental Therapeutics
Abstract
Gabexate mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation in which tumor necrosis factor-α (TNF-α) plays a critical role. We demonstrated that gabexate mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-α production in rats. In the present study, we analyzed the mechanism(s) by which gabexate mesilate inhibits LPS-induced TNF-α production in human monocytes in vitro. Gabexate mesilate inhibited the production of TNF-α in monocytes stimulated with LPS. Gabexate mesilate inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of inhibitory κBα. Gabexate mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that gabexate mesilate inhibited LPS-induced TNF-α production in human monocytes by inhibiting activation of both NF-κB and AP-1. Inhibition of TNF-α production by gabexate mesilate might explain at least partly its therapeutic effects in animals given LPS and those in patients with sepsis.