Hemorrhagic shock results in a disruption to systemic homeostasis and can eventually lead to multiple? organ dysfunction syndrome (MODS), which is the cause of 50-80% of deaths in the surgical intensive care? units. Because the development of MODS is poorly understood, current treatment is mainly supportive. It is? therefore critical to identify key events and factors that lead to the progression of MODS to identify critical points? of intervention.? The long-range goal of this research is to identify the factors released in response to shock that promote? systemic effects that contribute to the development of (MODS). This proposal focuses on the isolation and? identification of factor(s) that are present in mesenteric (intestinal) lymph and plasma following traumahemorrhagic? shock (T/HS) that suppress bone marrow (BM) cell colony formation, activate neutrophils, and? increase red blood cell rigidity. Our central hypothesis is that factors responsible for the BM, PMN and RBC? dysfunctions are produced in the gut after T/HS and introduced to the general circulation via the mesenteric? lymphatics. This is based on in vitro and in vivo data showing that suppression of BM cell colony formation,? PMN activation, and RBC rigidification is observed in rats subjected to T/HS but not T/SS and is abolished by? mesenteric lymph-duct ligation. Consequently, the primary goal of this project is to identify the biologically active? factors in the lymph and plasma by using a continuum of T/HS lymph/plasma separations where each subseparation? is tailored to the characteristics (e.g., protein, lipid, size, charge) of the components present in the? sub-fraction that retains toxicity. Identification of these factors will make it possible to study their production,? regulation, entry into the lymph and effects on different tissues. This research could help develop new? therapeutic modalities to prevent formation of or limit the damage produced by these factors in order to prevent? MODS.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM069790-02
Application #
7491776
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$197,721
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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
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
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
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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