ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

Abstract

ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. ONO 3403 significantly inhibited LPS-induced TNF-α production at a lower concentration than camostat mesilate. It also inhibited LPS-induced NO production. Their inhibition was responsible for the reduced mRNA expression of TNF-α and inducible NO synthase. In LPS-stimulated cells, ONO 3403 prevented the augmentation of MyD88 expression and inhibited the phosphorylation of IκB-α, stress-activated protein kinase (SAPK) and IRF-3, and the production of interferon-β. ONO 3403 abolished the elevation of the extracellular serine protease activity in response to LPS. Further, it reduced the circulating TNF-α level, hepatic injury and mortality in mice receiving an injection of D-galactosamine and LPS. ONO 3403 was suggested to inhibit LPS-induced inflammatory responses via inactivation of MyD88-dependent and independent pathways.

The clinically used serine protease inhibitor nafamostat reduces influenza virus replication and cytokine production in human airway epithelial cells and viral replication in mice

“…and with cell damage 34 . The results of the present study showing that treatment of cells with nafamostat reduced cytokine production are consistent with those of previous studies demonstrating the inhibitory effects of protease inhibitors, including camostat, gabexate, and aprotinin, 16,35,36 on cytokine production induced by influenza virus infection. These findings suggest that serine protease inhibitors may have anti‐inflammatory effects on the lungs and airways in the context of influenza virus infection.…”

The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells

“…Camostat and gabexate inhibit lipopolysaccharide (LPS)induced TNF release from macrophages [43], and also the development of influenza pneumonia in mice by inhibiting cytokine production, including IL-6 [44]. Aprotinin reduces ICAM-1 expression in human umbilical vein endothelial cells [45] and myocardial IL-6 gene expression after cardiac ischemia and reperfusion in rats [46].…”

High‐Volume Hemofiltration Reduces the Expression of Myocardial Tumor Necrosis Factor‐Alpha in Septic Shock Pigs

“…Early treatment with HVHF improved the environment, which in turn, might have reduced the endothelial cell NO synthesis (21). The decrease of plasma NO in animals receiving HVHF contributes to the amelioration of refractory hypotension in septic shock (22).…”