Original Contribution2-(2-Fluorobenzamido)benzoate ethyl ester (EFB-1) inhibits superoxide production by human neutrophils and attenuates hemorrhagic shock-induced organ dysfunction in rats

Add time:09/06/2019    Source:sciencedirect.com

Neutrophil activation after trauma–hemorrhagic shock (T/H) has been implicated in the development of multiple organ dysfunction (MOD). In this study, we report that a small chemical compound, 2-(2-fluorobenzamido)benzoic acid ethyl ester (EFB-1), exhibited a potent inhibitory effect on the formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP)-induced superoxide anion (O2•−) release and CD11b expression by human neutrophils. Additionally, administration of EFB-1 in rats subjected to T/H caused a significant improvement in MOD. EFB-1 treatment induced an increase in cAMP formation and protein kinase (PK) A activity in FMLP-activated neutrophils, which occurred through the selective inhibition of cAMP-specific phosphodiesterase (PDE) activity but not an increase in adenylate cyclase function or cGMP-specific PDE activity. FMLP-induced phosphorylation of protein kinase B (AKT), but not calcium mobilization, was reduced by EFB-1. The inhibitory effects of EFB-1 on O2•− production, CD11b expression, and AKT phosphorylation were reversed by PKA inhibitors (H89 and KT5720). Significantly, administration of EFB-1 (1 mg/kg body wt) attenuated the myeloperoxidase activity of the intestines, lungs, and liver and reduced the wet/dry weight ratio of the intestines and lungs and plasma alanine aminotransferase and aspartate aminotransferase levels in Sprague–Dawley rats after T/H. Therefore, EFB-1 is a new inhibitor of cAMP-specific PDE that potently suppresses O2•− release and CD11b expression by human neutrophils and attenuates T/H-induced MOD in rats.

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