title: 2-(2-Fluorobenzamido)benzoate ethyl ester (EFB-1) inhibits superoxide production by human neutrophils and attenuates hemorrhagic shock-induced organ dysfunction in rats.
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•-) 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 O(2•-) 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 O(2•-) release and CD11b expression by human neutrophils and attenuates T/H-induced MOD in rats.
authors: Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors: Huang-Ping
authors: HP
authors: Yu
authors: Pei-Wen
authors: PW
authors: Hsieh
authors: Yi-Ju
authors: YJ
authors: Chang
authors: Pei-Jen
authors: PJ
authors: Chung
authors: Liang-Mou
authors: LM
authors: Kuo
authors: Tsong-Long
authors: TL
authors: Hwang
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D039481:CD11b Antigen / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D005609:Free Radicals; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000293:injuries; D019272:Leukocyte Elastase / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000293:injuries; D055370:Lung Injury / Q000209:etiology / Q000517:prevention & control; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors*
chemical_list: C560790:2-(2-fluorobenzamido)benzoate ethyl ester; D001549:Benzamides; D001565:Benzoates; D039481:CD11b Antigen; D005609:Free Radicals; C509295:ITGAM protein, human; D013481:Superoxides; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D019272:Leukocyte Elastase; D000262:Adenylyl Cyclases