TY - JOUR
T1 - DSM-RX78, a new phosphodiesterase inhibitor, suppresses superoxide anion production in activated human neutrophils and attenuates hemorrhagic shock-induced lung injury in rats
AU - Yu, Huang Ping
AU - Hsieh, Pei Wen
AU - Chang, Yi Ju
AU - Chung, Pei Jen
AU - Kuo, Liang Mou
AU - Hwang, Tsong Long
PY - 2009/10/15
Y1 - 2009/10/15
N2 - 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{radical dot}-) 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{radical dot}- 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{radical dot}- production and Akt phosphorylation were reversed by PKA inhibitors, suggesting that DSM-RX78 regulates O2{radical dot}- 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.
AB - 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{radical dot}-) 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{radical dot}- 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{radical dot}- production and Akt phosphorylation were reversed by PKA inhibitors, suggesting that DSM-RX78 regulates O2{radical dot}- 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.
KW - Hemorrhagic shock
KW - Human neutrophils
KW - Methyl 2-(2-fluorobenzamido)benzoate
KW - Phosphodiesterase
KW - Superoxide anion
KW - cAMP
UR - http://www.scopus.com/inward/record.url?scp=69349102879&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2009.06.008
DO - 10.1016/j.bcp.2009.06.008
M3 - 文章
C2 - 19540209
AN - SCOPUS:69349102879
SN - 0006-2952
VL - 78
SP - 983
EP - 992
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 8
ER -