Abstract 2: Sodium-Hydrogen Exchanger Inhibition Attenuates Traumatic Hemorrhage Induced Acute Lung Injury in Pigs

Abstract

Background: Acute lung injury is a complication of traumatic hemorrhagic shock, and contributes to the high mortality rate. This study examined the effects of Na+/H+ exchanger inhibition on traumatic hemorrhage induced acute lung injury in pigs. Methods: Tibia fractures with soft tissue injury were induced in 12 anesthetized instrumented male pigs. The animals underwent hemorrhage of 25ml/kg for 20min, followed by a 4mm abdominal aortic tear with surgical repair after 30minutes. Animals then underwent initial fluid resuscitation with either 15ml/kg Hextend (n=6) or 3mg/kg BIIB513 +15ml/kg Hextend (n=6). Resuscitation occurred over 40 minutes. A second resuscitation was given 4 hours later. Hemodynamics, arterial and mix-venous blood gases were measured throughout the experiment, which was terminated 6 hours after initial resuscitation. Results: Hemorrhage and resuscitation with Hextend alone resulted in a significant increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). These changes were accompanied by a significant decrease in mix-venous oxygen saturation, decreased oxygen delivery and an increased oxygen extraction ratio. BIIB513 + Hextend treatment significantly attenuated the increase in PAP by 26% and PVR by 50%, as well as significantly improving blood oxygen delivery by 30%. BIIB513+ Hextend treatment group had a 70% higher blood oxygen content and mixed venous blood oxygen saturation than did the control group (61% vs. 42%). NHE-1 inhibition with BIIB513 reduced lung tissue levels of IL-6 by 80%, TNF-á by 37%, and myeloperoxidase activity by 38%. Nuclear factor (NF)-ê B DNA binding activity in the lung was slightly attenuated in BIIB513 treated animals), compared to those treated with hextend alone. Conclusion : The present study shows that the response to fluid resuscitation after controlled hemorrhage is improved by the addition of the NHE-1 inhibitor BIIB513. NHE-1 inhibition resulted in attenuation of traumatic hemorrhage and resuscitation induced acute lung injury by improving pulmonary vascular function, possibly by reducing NF-κB activation and neutrophil infiltration, thereby limiting the tissue inflammatory injury.