The new knowledge of polymorphonuclear neutrophil (PMN) signaling in relation to effector responses, and their transcriptional and cell-cell interactive capabilities, affords the opportunity to expand investigations of PMN adaptive and inappropriate roles in burn/ trauma and sepsis injury conditions. This study will focus on PMN signaling, cytokine expression and cell-cell interactions during burn injury complicated by Enterococcus faecalis infection. The latter organism has been increasingly recognized as a pathogen causing serious morbidity in intensive care patients. Our recent studies have shown that inoculation of E. faecalis in burned rats produces hemodynamic instability and mortality not seen with the individual burn or E. faecalis challenges. Our previous and preliminary studies have shown burn injury alone causes upregulation of PMNs' signaling, contributing to their enhanced oxidant production, protease release and adhesion to endothelial cells. We hypothesize that PMNs' tissue damaging actions, via oxidant production, protease release, and cell-cell interactions, are exacerbated to produce the animal morbidity and mortality with combined burn and E. faecalis injuries. The investigation of mechanisms of PM""""""""s inappropriate portentiated responses will be carried out in a rat model of 30 percent total body surface area burn plus an intraabdominal inoculation of Enterococcus faecalis using two strains of the organism, one expressing and one not expressing the AS (Aggregation Substance) protein which has been implicated in enhancing E. faecalis virulence.
Specific aim 1 will establish linkage between potentiated oxidant production, elastase release, adhesion to endothelial cells, and altered apoptosis of PMNs to ithe signaling pathways involving protein tyrosine kinases (PTK), phophtidylinositol 3-kinase (PI-3K), and mitogen- lactivated protein kinases (MAPK), Erk and p38. The approach in this aim would be to determine if in vivo administrations of signaling blocker agents to the injured animals result in an attenuatiodprevention of the potentiated PMN effector response.
Specific aim 2 will assess if PMN transmigration across endothelial and epithelial barriers are altered and whether such alterations are related to PMN release of elastase causing damage to the endothelial and/or epithelial adherense junctions by hydrolyzing the junction protein cadherin.
Specific aim 3 will evaluate PMN expression of chemokines, CINC, MIP-2 and MIPl a, and proinflammatory cytokines, IL-1beta, IL-6, and their autocrine/paracrine potentiation of PMN chemotaxis and anti-apoptotic behavior.
Specific aim 4 is to evaluate the relevance of potentiated effector responses by PMNs in producing damage to structural/functional integrity of intestine, and their relevance to hemodynamic instability and mortality in the burned-E. faecalis infected animals. The proposed studies will enhance our understanding of the role of potentiated PMN effector responses in causing host morbidity and mortality in burn injury complicated by enterococcal infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056865-06
Application #
6604745
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1998-07-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2003
Total Cost
$296,000
Indirect Cost
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Fazal, Nadeem; Choudhry, Mashkoor A; Sayeed, Mohammed M (2005) Inhibition of T cell MAPKs (Erk 1/2, p38) with thermal injury is related to down-regulation of Ca2+ signaling. Biochim Biophys Acta 1741:113-9
Hu, Zhihong; Sayeed, Mohammed M (2005) Activation of PI3-kinase/PKB contributes to delay in neutrophil apoptosis after thermal injury. Am J Physiol Cell Physiol 288:C1171-8
Samonte, Victoria A; Goto, Masakatsu; Ravindranath, Thyyar M et al. (2004) Exacerbation of intestinal permeability in rats after a two-hit injury: burn and Enterococcus faecalis infection. Crit Care Med 32:2267-73
Al-Ghoul, Walid M; Khan, Mehdi; Fazal, Nadeem et al. (2004) Mechanisms of postburn intestinal barrier dysfunction in the rat: roles of epithelial cell renewal, E-cadherin, and neutrophil extravasation. Crit Care Med 32:1730-9
Hu, Zhihong; Sayeed, Mohammed M (2004) Suppression of mitochondria-dependent neutrophil apoptosis with thermal injury. Am J Physiol Cell Physiol 286:C170-8
Dallal, Ousama; Ravindranath, Thyyar M; Choudhry, Mashkoor A et al. (2003) T-cell proliferative responses following sepsis in neonatal rats. Biol Neonate 83:201-7
Choudhry, Mashkoor A; Haque, Farah; Khan, Mehdi et al. (2003) Enteral nutritional supplementation prevents mesenteric lymph node T-cell suppression in burn injury. Crit Care Med 31:1764-70
Choudhry, Mashkoor A; Fazal, Nadeem; Goto, Masakatsu et al. (2002) Gut-associated lymphoid T cell suppression enhances bacterial translocation in alcohol and burn injury. Am J Physiol Gastrointest Liver Physiol 282:G937-47

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