Sepsis and noninfectious inflammation lead to organ dysfunction and death in greater than 230,000 people annually in the United States alone. Recent studies demonstrate that sepsis and noninfectious inflammation induce excess intestinal epithelial apoptosis in both animal models of critical illness and in human autopsy studies. The central hypothesis of this new laboratory is that increased gut epithelial apoptosis is detrimental in critical illness, and that decreasing levels of cell death will improve experimental survival. Since previous descriptive studies showing elevated intestinal epithelial apoptosis in sepsis and noninfectious inflammation cannot distinguish whether altered gut apoptosis has a functional significance in critical illness, the first aim of this investigation is to demonstrate that inhibiting gut epithelial apoptosis through mechanistically distinct strategies decreases mortality in diverse models of critical illness. Gut epithelial apoptosis will be selectively targeted using transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Gut-directed caspase inhibitors will also be utilized. These apoptosis- inhibition strategies will be complemented with a novel apoptosis-acceleration strategy using the antilymphocyte antibody, anti-CD3 which causes a 40-fold induction of gut epithelial apoptosis. Mechanisms that may underlie the survival advantage conferred by a decrease in gut apoptosis will be investigated as well. Gut permeability studies will be performed using the ex vivo everted gut sac model on transgenic animals that overexpress intestinal Bcl-2 and their control littermates after induction of sepsis or noninfectious inflammation and. Interactions with the immune system will be assessed by the development of mice that simultaneously overexpress Bcl-2 in their intestinal epithelium but are deficient for T- and B- lymphocytes (Rag-1 mice). Throughout these studies, four models of critical illness will be utilized varying the site of injury (intraabdominal vs. lung) and type of infection (polymicrobial vs. monomicrobial).

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Liang, Zhe; Xie, Yan; Dominguez, Jessica A et al. (2014) Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice. PLoS One 9:e101828
Jung, Enjae; Perrone, Erin E; Brahmamdan, Pavan et al. (2013) Inhibition of intestinal epithelial apoptosis improves survival in a murine model of radiation combined injury. PLoS One 8:e77203
Dominguez, Jessica A; Samocha, Alexandr J; Liang, Zhe et al. (2013) Inhibition of IKK* in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality. Crit Care Med 41:e275-85
Hunter, Rebecca A; Privett, Benjamin J; Henley, W Hampton et al. (2013) Microfluidic amperometric sensor for analysis of nitric oxide in whole blood. Anal Chem 85:6066-72
Benton, Shana M; Liang, Zhe; Hao, Li et al. (2012) Differential regulation of tissue thiol-disulfide redox status in a murine model of peritonitis. J Inflamm (Lond) 9:36
Dominguez, Jessica A; Xie, Yan; Dunne, W Michael et al. (2012) Intestine-specific Mttp deletion decreases mortality and prevents sepsis-induced intestinal injury in a murine model of Pseudomonas aeruginosa pneumonia. PLoS One 7:e49159
Perrone, Erin E; Jung, Enjae; Breed, Elise et al. (2012) Mechanisms of methicillin-resistant Staphylococcus aureus pneumonia-induced intestinal epithelial apoptosis. Shock 38:68-75
Fox, Amy C; McConnell, Kevin W; Yoseph, Benyam P et al. (2012) The endogenous bacteria alter gut epithelial apoptosis and decrease mortality following Pseudomonas aeruginosa pneumonia. Shock 38:508-14
Jung, Enjae; Perrone, Erin E; Liang, Zhe et al. (2012) Cecal ligation and puncture followed by methicillin-resistant Staphylococcus aureus pneumonia increases mortality in mice and blunts production of local and systemic cytokines. Shock 37:85-94
Fox, Amy C; Breed, Elise R; Liang, Zhe et al. (2011) Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality. J Immunol 187:1950-6

Showing the most recent 10 out of 51 publications