Trauma is the leading cause of death in people under the age of 40 and MODS is the leading cause ofdeath in trauma patients surviving the initial 72 hour injury period. In fact, MODS is the leading cause ofdeath in ICUs today. Although still somewhat controversial, there is recent evidence that the response toinjury and sepsis may differ between males and females, with females being more resistant to the adverseconsequences of T/HS than males. Thus, understanding the mechanisms by which trauma-hemorrhagicshock (T/HS) leads to MODS, as well as the role of sex hormones in modulating this response, is of majorhealth importance. This Project will follow up on our results indicating that male, but not female, ratsdevelop T/HS-induced lung injury and endothelial cell activation/injury by testing the following twohypotheses. The first hypothesis is that T/HS-induced lung injury and increased endothelial cellpermeability is secondary to gut injury and is mediated by factors exiting the gut via the mesentericlymphatics but not the portal vein. The second hypothesis is that sex hormones modulate gut and hencedistant organ injury in a model of T/HS. To test these hypotheses, we will first investigate the potentialmechanisms of why the female gut is more resistant than the male gut to T/HS-induced gut injury and doesnot produce toxic lymph. Next, we will investigate the role of sex hormones asmodulators of resistance and susceptibility to T/HS-induced gut and lung injury. We willinvestigate the hypothesis that estrogen protects against T/HS-induced gut injury by limiting iNOSinduction. Lastly, we will investigate the mechanisms by which T/HS mesenteric lymph, alone or incombination with PMNs, increases vascular permeability and how this is influenced by gonadal hormonalmanipulation.
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