Traumatic injuries are a leading cause of death. While early deaths are secondary to hemorrhage, late deaths are attributed to multiple organ failure (MOF). The institution of early enteral nutrition with immune enhancing nutrients (lEN's) has been shown to decrease infectious morbidity and therefore lessen the incidence of late post-injury MOF. Their use in critically ill patients, however, has been called into question, as mortality may be increased in this patient population. Arginine, as a substrate for nitric oxide, has been implicated in causing harm in patients in whom iNOS is activated. The mechanisms by which each of the lEN's exert their effect on the postischemic gut is unclear. While our data suggests that enteral glutamine may be protective to the postischemic gut through the activation of PPARgamma, we have also shown that arginine under these same conditions is harmful via activation of nitric oxide as well as through selective activation of AP-1 (but not NFKB) via the c-jun/ MARK pathway. Although our long range goal is to elucidate the mechanisms by which each IEN modulates both the local (gut) and systemic response to inflammation, the current proposal will focus only on investigating the local effects of glutamine and arginine in the post- ischemic gut. The overall hypothesis is that enteral glutamine is protective to the postischemic gut through activation of PPARgamma and that enteral arginine is injurious through activation of iNOS and AP-1.
Aim 1 and 2 are mechanistic and will further investigate the novel role of PPARgamma in the protective effect afforded by glutamine and the selective activation of AP-1 and iNOS through the nitric oxide-mediated protein kinase G pathway in the injurious effect of arginine.
Aim 3 will examine the consequences of admin- istration of arginine and glutamine in combination when delivered as synchronous and salvage therapy to the postischemic gut. Using a rodent model of gut ischemia/reperfusion and a cell culture model of oxidant stress along with sophisticated molecular techniques, these studies will important insight into the molecular mechanisms governing the expression of gene products expressed in the postischemic gut and how these nutrients harm or protect the gut. It is anticipated this study will provide the basis for the rationale design of clinical trials to specifically address the optimal enteral nutrients for adiministration to critically injured patients during periods of gut hypoperfusion and may therefore lessen the incidence of postinjury MOF.
|Peng, Zhanglong; Ban, Kechen; Wawrose, Richard A et al. (2015) Protection by enteral glutamine is mediated by intestinal epithelial cell peroxisome proliferator-activated receptor-? during intestinal ischemia/reperfusion. Shock 43:327-33|
|Ban, Kechen; Peng, Zhanglong; Kozar, Rosemary A (2013) Inhibition of ERK1/2 worsens intestinal ischemia/reperfusion injury. PLoS One 8:e76790|
|Ban, Kechen; Peng, Zhanglong; Lin, Wei et al. (2012) Arginine decreases peroxisome proliferator-activated receptor-? activity via c-Jun. Mol Cell Biochem 362:7-13|
|Peng, Zhanglong; Ban, Kechen; Sen, Aritra et al. (2012) Syndecan 1 plays a novel role in enteral glutamine's gut-protective effects of the postischemic gut. Shock 38:57-62|
|Ban, Kechen; Kozar, Rosemary A (2012) Protective role of p70S6K in intestinal ischemia/reperfusion injury in mice. PLoS One 7:e41584|
|Ban, Kechen; Sprunt, Julie M; Martin, Stephanie et al. (2011) Glutamine activates peroxisome proliferator-activated receptor-ýý in intestinal epithelial cells via 15-S-HETE and 13-OXO-ODE: a novel mechanism. Am J Physiol Gastrointest Liver Physiol 301:G547-54|
|Kozar, Rosemary A; Santora, Rachel J; Poindexter, Brian J et al. (2011) Alterations in content and localization of defensins in rat ileum and jejunum following ischemia-reperfusion. Specific peptides, in specific places, for specific jobs? Eplasty 11:e8|
|Ban, Kechen; Santora, Rachel; Kozar, Rosemary A (2011) Enteral arginine modulates inhibition of AP-1/c-Jun by SP600125 in the postischemic gut. Mol Cell Biochem 347:191-9|
|Santora, Rachel; Kozar, Rosemary A (2010) Molecular mechanisms of pharmaconutrients. J Surg Res 161:288-94|
|Ban, Kechen; Kozar, Rosemary A (2010) Glutamine protects against apoptosis via downregulation of Sp3 in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 299:G1344-53|
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