Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8271767 | Free Radical Biology and Medicine | 2011 | 12 Pages |
Abstract
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
- â) 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
- â production, CD11b expression, and AKT phosphorylation were reversed by PKA inhibitors (H89 and KT5720). Significantly, administration of EFB-1 (1Â 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
- â release and CD11b expression by human neutrophils and attenuates T/H-induced MOD in rats.
- â) 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
- â production, CD11b expression, and AKT phosphorylation were reversed by PKA inhibitors (H89 and KT5720). Significantly, administration of EFB-1 (1Â 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
- â release and CD11b expression by human neutrophils and attenuates T/H-induced MOD in rats.
Keywords
fMLPPKCGPCRpKaPDEMODSPAPGE1WST-1IBMXCytochalasin Bt/h3-isobutyl-1-methylxanthinecAMPMPOG-protein-coupled receptorPMAO2•−ROScyclic adenosine 3′,5′-monophosphateadenylate cyclasesuperoxide anionAktMultiple organ dysfunctionScintillation proximity assayFree radicalsSODSuperoxide dismutasephorbol myristate acetatePhosphodiesteraselactate dehydrogenaseLDHmyeloperoxidaseNeutrophilsprotein kinase Aprotein kinase BProtein kinase CProstaglandin E1Reactive oxygen species
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Authors
Huang-Ping Yu, Pei-Wen Hsieh, Yi-Ju Chang, Pei-Jen Chung, Liang-Mou Kuo, Tsong-Long Hwang,