Mechanisms of the beneficial effect of NHE1 inhibitor in traumatic hemorrhage: Inhibition of inflammatory pathways

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 4 mm hepatic arterial tear with surgical repair after 20 min. Animals then underwent low volume fluid resuscitation with either hextend (n = 6) or 3 mg/kg BIIB513 (NHE1 inhibitor) + hextend (n = 6). The experiment was terminated 6 h 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.