Acute Lung Injury after Hemorrhagic Shock is Dependent on Gut Injury and Sex

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Abstract
Recent studies have established gut-derived lymph rather than portal blood as the major source of toxic mediators after hemorrhagic shock that causes distant organ injury. Similarly, emerging data have identified sex as a major modifier of the response to injury and illness. Thus we tested the hypothesis that female rats would be more resistant to shock-induced lung injury than male rats because females are more resistant to shock-induced gut injury and produce mesenteric lymph that is less toxic to endothelial cells. Male and female rats were subjected to sham or hemorrhagic shock and lung permeability was quantitated by Evans blue dye and protein extravasation into the alveolar space. Next, mesenteric lymph collected from shocked and sham-shocked rats of both sexes was incubated with human umbilical vein endothelial cells (HUVECs) and assayed for toxicity. Trypan blue dye exclusion and the release of lactate dehydrogenase assessed HUVEC viability and injury respectively. Lastly, sections of the terminal ileum were histologically examined for evidence of shock-induced mucosal injury. Male rats but not female rats subjected to hemorrhagic shock had evidence of increased lung permeability and produced mesenteric lymph that was cytotoxic to HUVECs. Shock caused gut injury in the male rats whereas histological evidence of gut injury was not observed in the female rats. Hemorrhagic shock-induced lung injury depends on gut injury and mesenteric lymph appears to be the route by which gut-derived toxic factors exit the gut to cause lung injury. The resistance of female rats to shock-induced lung injury appears to be secondary to their resistance to shock-induced gut injury.