title: Mechanisms of the beneficial effect of NHE1 inhibitor in traumatic hemorrhage: inhibition of inflammatory pathways.
abstract: This study evaluated the effects of sodium-hydrogen exchanger (NHE1) inhibition on enhancing fluid resuscitation outcomes in traumatic hemorrhagic shock, and examined the mechanisms related to NHE1 inhibitor-induced protection and recovery from hemorrhagic shock. Traumatic hemorrhage was modeled in anesthetized pigs by producing tibia fractures followed by hemorrhage of 25 ml/kg for 20 min, and then a 4mm hepatic arterial tear with surgical repair after 20 min. Animals then underwent low volume fluid resuscitation with either hextend (n=6) or 3mg/kg BIIB513 (NHE1 inhibitor)+hextend (n=6). The experiment was terminated 6h after the beginning of resuscitation. In association with traumatic hemorrhagic shock, there was a decrease in cardiac index, stimulation of the inflammatory response, myocardial, liver and kidney injury. The administration of the NHE1 inhibitor at the time of resuscitation attenuated shock-resuscitation-induced myocardial hypercontracture and resulted in a significant increase in stroke volume index, compared to vehicle-treated controls. NHE1 inhibition also reduced the inflammatory response, and lessened myocardial, liver and kidney injury. In addition, NHE1 inhibition reduced NF-κB activation and iNOS expression, and attenuated of ERK1/2 phosphorylation. Results from the present study indicate that NHE1 inhibition prevents multiple organ injury by attenuating shock-resuscitation-induced myocardial hypercontracture and by inhibiting NF-κB activation and neutrophil infiltration, reducing iNOS expression and ERK1/2 phosphorylation, thereby, reducing systemic inflammation and thus multi-organ injury.
authors.affiliation: Department of Research, Mount Sinai Medical Center, Miami Beach, FL 33140, USA. dongmeiwu@bellsouth.net
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.forename: Jiansong
authors.initials: J
authors.lastname: Qi
mesh_terms: D000818:Animals; D005440:Fluid Therapy; D006439:Hemodynamics; D006895:Hydroxyethyl Starch Derivatives / Q000627:therapeutic use; D007249:Inflammation / Q000517:prevention & control; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D020935:MAP Kinase Signaling System; D008297:Male; D008698:Mesylates / Q000627:therapeutic use*; D009102:Multiple Organ Failure / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000517:prevention & control; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D010952:Plasma Substitutes / Q000627:therapeutic use; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology / Q000628:therapy; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D034421:Sus scrofa; D019210:Troponin I / Q000097:blood
chemical_list: D006895:Hydroxyethyl Starch Derivatives; D015850:Interleukin-6; D008698:Mesylates; D016328:NF-kappa B; D010952:Plasma Substitutes; D017923:Sodium-Hydrogen Exchangers; D019210:Troponin I; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II; C402725:BIIB 513