Trauma is the leading cause of death in people under the age of 40 and MODS is the leading cause of death in intensive care units. Consequently, understanding the mechanisms by which trauma-hemorrhagic shock (T/HS) leads to MODS is of major health importance in this country. One of the major hypotheses being studied to explain the development of sepsis and MODS after trauma is the gut hypothesis of MODS. Additionally, there is recent experimental and clinical information that the response to injury and sepsis may differ between males and females. Thus, the overall global hypothesis of this grant is that trauma hemorrhagic (T/HS) shock-induced early distant organ injury and cellular dysfunction is secondary to gut injury and is primarily mediated by factors exiting the gut via the mesenteric lymphatics. Our secondary major hypothesis is that gender and sex hormones modulate gut and hence distant organ and cellular dysfunction after T/HS. These hypotheses are supported by our preliminary studies indicating that T/HSinduced lung injury and endothelial cell activation/dysfunction (Project by Deitch), neutrophil activation (Project by Hauser), red blood cell dysfunction (Project by MachiedoI) and bone marrow failure (Project by Kaiser) in male rats are mediated primarily by factors exiting the gut in the mesenteric lymph. Additionally, our studies show that proestrus female rats are resistant to these T/HS-induced injuries. Based on these results showing that female rats are more resistant to T/HS than male rats, the effects of gender and sex hormone modulation on cellular and organ dysfunction will be investigated. In all of the Projects, the mechanisms by which T/HS leads to these changes will be studied. Since T/HS-induced gut injury appears to be the initiating injury that induces this cascade of events, both Project by Deitch and Project by Feinman, will focus on determining the mechanisms by which T/HS leads to gut injury. Additionally, focused human studies in trauma patients will be carried out investigating trauma-induced neutrophil activation (Project by Hauser) and RBC dysfunction (Project by Machiedo). In summary, these projects will provide insight into the early mechanisms by which T/HS predisposes to MODS and will clarify the roles of gender and sex hormones as modulators of this response. The Administrative Core will serve to coordinate the activities of the various projects as well as be an information nexus, while the Animal Models Core will ensure consistency of the models being used and facilitate integration of the results obtained as well as reduce the costs of the overall proposal. The Human Core will serve to facilitate translational studies as well as aid in correlating the results of the human and animal studies. Lastly, Project by Kaiser focusing on factor isolation has been included to answer the question of what are the factors present in T/HS mesenteric lymph that are causing these changes in neutrophil, RBC and bone marrow function.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Specialized Center (P50)
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Special Emphasis Panel (ZGM1-PPBC-5 (TB))
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Somers, Scott D
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University of Medicine & Dentistry of NJ
Schools of Medicine
United States
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Reino, Diego C; Palange, David; Feketeova, Elenora et al. (2012) Activation of toll-like receptor 4 is necessary for trauma hemorrhagic shock-induced gut injury and polymorphonuclear neutrophil priming. Shock 38:107-14
Sheth, Sharvil U; Palange, David; Xu, Da-Zhong et al. (2011) Testosterone depletion or blockade in male rats protects against trauma hemorrhagic shock-induced distant organ injury by limiting gut injury and subsequent production of biologically active mesenteric lymph. J Trauma 71:1652-8
Reino, Diego C; Pisarenko, Vadim; Palange, David et al. (2011) Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice. PLoS One 6:e14829
Kannan, Kolenkode B; Colorado, Iriana; Reino, Diego et al. (2011) Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury. Am J Physiol Gastrointest Liver Physiol 300:G853-61
Condon, Michael; Senthil, Maheswari; Xu, Da-Zhong et al. (2011) Intravenous injection of mesenteric lymph produced during hemorrhagic shock decreases RBC deformability in the rat. J Trauma 70:489-95
Qin, Yong; Prescott, Lauriston M; Deitch, Edwin A et al. (2011) Heparin use in a rat hemorrhagic shock model induces biologic activity in mesenteric lymph separate from shock. Shock 35:411-21
Sharpe, Susan M; Qin, Xiaofa; Lu, Qi et al. (2010) Loss of the intestinal mucus layer in the normal rat causes gut injury but not toxic mesenteric lymph nor lung injury. Shock 34:475-81
Doucet, Danielle; Badami, Chirag; Palange, David et al. (2010) Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats. PLoS One 5:e9421
Doucet, Danielle R; Bonitz, R Paul; Feinman, Rena et al. (2010) Estrogenic hormone modulation abrogates changes in red blood cell deformability and neutrophil activation in trauma hemorrhagic shock. J Trauma 68:35-41
Mohr, Alicia M; Lavery, Robert F; Sifri, Ziad C et al. (2010) Gender differences in glucose variability after severe trauma. Am Surg 76:896-902

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