Trauma is the leading cause of death between the ages of 1 and 45. Between the ages of 1 and 36, death? from trauma exceeds all other causes of death combined. Of the 50,000 victims per year in the USA who survive? trauma early on only to die later, most die when trauma and hemorrhagic shock (T/HS) trigger the Systemic? Inflammatory Response Syndrome (SIRS). Shock leads to SIRS when low-flow followed by reperfusion injures? the gut, causing the synthesis of inflammatory mediators which can then enter the systemic circulation via? intestinal lymphatics.? Neutrophils (PMN) are key effector cells in early immune responses to injury. They are critical participants? both in organ failure and in responses to infection. PMN are susceptible to activation by gut lymph and other? inflammatory stimuli, yet PMN dysfunction in SIRS can be clinically manifest either as hyper-activation and organ? failure or as hypo-function and sepsis. Thus aberrant PMN responses after exposure to T/HS lymph are a major? public health problem, but they are complex and incompletely characterized. Our recent work suggests that PMN? mediated inflammation is critically regulated by entry of calcium into the cell which is dependent on a process? called Store-Operated Calcium Entry (SOCE). We have also shown that SOCE in turn, is regulated by a class of? molecules called the lysophospholipids (LPL). Preliminary data suggests that PMN responses to LPL play a? critical role in the immune complications of trauma, that PMN responses to LPL are strongly regulated by T/HS,? and that blocking either the synthesis or the calcium mobilizing effects of LPL diminishes PMN activation and? prevents organ failure after shock.? This proposal therefore seeks to determine how gut lymph-mediated systemic inflammation modifies? LPL signaling in PMN, how such signaling modification may affect PMN function, and whether inhibition of LPL? synthesis or LPL-dependent SOCE can prevent the pathologic PMN responses to T/HS gut lymph which? predispose to organ injury and sepsis. In addition, since alterations in PMN function subsequent to T/HS are? often gender specific, we will determine which aspects of gut lymph-related LPL signal dysfunction in the PMN? depend upon gender and hormonal milieu. This information will help us later to optimize use of LPL and SOCE? inhibition in specific trauma populations.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Medicine & Dentistry of NJ
United States
Zip Code
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

Showing the most recent 10 out of 23 publications