DSM-RX78, a new phosphodiesterase inhibitor, suppresses superoxide anion production in activated human neutrophils and attenuates hemorrhagic shock-induced lung injury in rats |
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Authors: | Huang-Ping Yu Pei-Wen Hsieh Pei-Jen Chung Tsong-Long Hwang |
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Institution: | a Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan b College of Medicine, Chang Gung University, Taoyuan 333, Taiwan c Graduate Institute of Natural Products, Chang Gung University, Taoyuan 333, Taiwan d Department of General Surgery, Chang Gung Memorial Hospital at Chia-Yi, Taiwan |
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Abstract: | Neutrophils are activated following hemorrhagic shock and the accumulation of neutrophils in the lung is associated with lung injury. This research investigated the effects of a semisynthetic 2-benzoylaminobenzoic acid derivative, methyl 2-(2-fluorobenzamido)benzoate (DSM-RX78), on superoxide anion (O2−) production in formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP)-activated human neutrophils, and on lung injury in Sprague-Dawley rats subjected to trauma-hemorrhage. DSM-RX78 concentration-dependently inhibited O2− production, but not elastase release, in FMLP-activated human neutrophils. DSM-RX78 displayed no superoxide-scavenging ability, and it failed to alter the subcellular NADPH oxidase activity. Significantly, DSM-RX78 increased 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. These results show that DSM-RX78 is a new inhibitor of cAMP-specific PDE. Moreover, DSM-RX78 reduced FMLP-induced phosphorylation of protein kinase B (Akt), but not calcium mobilization. The inhibitory effects of DSM-RX78 on O2− production and Akt phosphorylation were reversed by PKA inhibitors, suggesting that DSM-RX78 regulates O2− production of human neutrophils by promoting cAMP/PKA-dependent inhibition of Akt activation. On the other hand, administration of DSM-RX78 significantly attenuated the increase in myeloperoxidase activity and edema in the lung, as well as protein concentrations in bronchoalveolar lavage fluid in rats after trauma-hemorrhagic shock. In summary, these results strongly suggest that DSM-RX78 exerts anti-inflammatory effects, which result from the elevation of cAMP levels and PKA activity through its inhibition of cAMP-specific PDE. Also, our findings show that DSM-RX78 attenuates hemorrhagic shock-induced lung injury in rats. |
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Keywords: | AC adenylyl cyclase Akt protein kinase B ARDS acute respiratory distress syndrome cAMP cyclic adenosine 3&prime 5&prime -monophosphate CB cytochalasin B COPD chronic obstructive pulmonary disease FMLP l-methionyl-l-leucyl-l-phenylalanine" target="_blank">formyl-l-methionyl-l-leucyl-l-phenylalanine GPCR G protein-coupled receptor H89 N-(2-((p-bromocinnamyl)amino)ethyl)-5-isoquinolinesulfonamide IBMX 3-isobutyl-1-methylxanthine KT5720 9S 10S 12R-2 3 9 10 11 12-hexahydro-10-hydroxy-9-methyl-1-oxo-9 12-epoxy-1H-diindolo(1 2 3-fg:3&prime 2&prime 1&prime -kl)pyrrolo(3 4-i)(1 6)benzodiazocine-10-carboxylic acid hexyl ester MPO myeloperoxidase O2els-cdn &minus" target="_blank">com/sd/entities/rad" class="glyphImg">&minus superoxide anion PDE phosphodiesterase PKA protein kinase A PKC protein kinase C LDH lactate dehydrogenase PMA phorbol myristate acetate Ro318220 3-(1-(3-(amidinothio)propyl-1H-indol-3-yl))-3-(1-methyl-1H-indol-3-yl)maleimide SOD superoxide dismutase SPA scintillation proximity assay WST-1 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2 4-disulfophenyl)-2H-tetrazolium monosodium salt |
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