Inhibitors of NADPH oxidase reduce the organ injury in hemorrhagic shock.
Reactive oxygen species contribute to the multiple organ dysfunction syndrome in hemorrhagic shock. Here, we investigate the effects of two chemically distinct inhibitors of NADPH oxidase on the circulatory failure and the organ dysfunction and injury associated with hemorrhagic shock in the anesthetized rat. Hemorrhage (sufficient to lower mean arterial blood pressure of 45 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure and in renal dysfunction and liver injury. Treatment of rats upon resuscitation with the NADPH oxidase inhibitors diphenylene iodonium (DPI, 1 mg/kg i.v.) reduced renal dysfunction and liver injury, whereas apocynin (3 mg/kg i.p.) did reduce the liver injury, but not the renal dysfunction caused by hemorrhagic shock. DPI and apocynin also attenuated the lung and intestinal injury (determined by histology) caused by hemorrhage and resuscitation. In the liver, DPI and apocynin abolished the increase in the formation of superoxide anions associated with hemorrhagic shock. However, neither DPI nor apocynin had a significant effect on the delayed circulatory failure caused by hemorrhage and resuscitation. In addition, DPI and apocynin did not reduce the increase in nitric oxide synthesis caused by hemorrhagic shock. Moreover, DPI reduced the activation of the transcription factor activator protein-1 caused by severe hemorrhage and resuscitation in the liver. Thus, we propose that an enhanced formation of superoxide anions by NADPH oxidase contributes to the liver injury caused by hemorrhagic shock, and that inhibitors of NADPH oxidase may represent a novel therapeutic approach for the therapy of hemorrhagic shock.
Abdelrahman
Maha
M
Centre of Experimental Medicine, Nephrology, and Critical Care, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London EC1M 6BQ, UK.
Mazzon
Emanuela
E
Bauer
Michael
M
Bauer
Inge
I
Delbosc
Sandrine
S
Cristol
Jean-Paul
JP
Patel
Nimesh S A
NS
Cuzzocrea
Salvatore
S
Thiemermann
Christoph
C
D000098:Acetophenones / Q000494:pharmacology; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D007422:Intestines / Q000293:injuries; D007668:Kidney / Q000293:injuries / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D055370:Lung Injury; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000097:blood / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000098:Acetophenones; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D013481:Superoxides; D009569:Nitric Oxide; C007517:diphenyleneiodonium; D004247:DNA; D003404:Creatinine; C056165:acetovanillone; D019255:NADPH Oxidases; D000410:Alanine Transaminase