Gut epithelial apoptosis is increased in both animal models and human autopsy studies of sepsis. This appears to be physiologically significant since overexpression of either the anti-apoptotic protein Bcl-2 or the cytoprotective peptide EGF in the intestinal epithelium inhibits apoptosis and improves survival in murine models of sepsis. The mechanisms through which prevention of gut apoptosis improves survival are unclear. This proposal examines the relationship between gut apoptosis and other determinants of gut integrity in sepsis. Under homeostatic conditions, cells proliferate in the crypt, migrate up the villus and then die by apoptosis in a cycle that occurs over 3-5 days. In addition to increased gut apoptosis, sepsis leads to markedly decreased gut epithelial proliferation. This proposal will test whether proliferation is dependent on apoptosis in sepsis by measuring proliferation in animals with increased or decreased sepsis-induced gut epithelial apoptosis and testing mechanisms that potentially control gut proliferation. In light of significantly different signaling pathways between the proliferative crypt and differentiated villus, the importance of the crypt/villus microenvironment will also be tested by studying the relationship between proliferation and apoptosis in transgenic animals that have ectopic villus proliferation. Another important determinant of gut integrity is gut barrier function. Sepsis induces gut barrier failure with intestinal hyperpermeability which can result in harmful antigens and bacteria escaping the lumen and perpetuating the systemic inflammatory response syndrome. This proposal will determine whether changes in the tight junction with resultant changes in permeability are dependent upon gut apoptosis. This will be done by measuring permeability and expression of tight junction mediators in animals with increased or decreased sepsis- induced gut epithelial apoptosis. Further, mechanisms that potentially control sepsis- induced intestinal hyperpermeability will be assayed. Finally, we have shown that while sepsis induces gut apoptosis, this is further augmented in the absence of lymphocytes, demonstrating that lymphocytes play an anti-apoptotic role on the gut epithelium in sepsis. The mechanisms underlying lymphocyte control of sepsis-induced gut apoptosis are unknown, and this proposal seeks to clarify them in highly translational models of sepsis.
Gut apoptosis is markedly increased in sepsis, a disease that kills 210,000 people annually in the United States. Increased gut apoptosis appears to be functionally significant since preventing gut apoptosis improves survival in animal studies of sepsis;however, the mechanisms responsible for this are unknown. Understanding how sepsis- induced gut apoptosis alters overall intestinal integrity may therefore have significant therapeutic implications in a disease that is the most common killer in intensive care units.
|Mittal, Rohit; Wagener, Maylene; Breed, Elise R et al. (2014) Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy. PLoS One 9:e93523|
|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|
|Mittal, Rohit; Coopersmith, Craig M (2014) Redefining the gut as the motor of critical illness. Trends Mol Med 20:214-23|
|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|
|Yoseph, Benyam P; Breed, Elise; Overgaard, Christian E et al. (2013) Chronic alcohol ingestion increases mortality and organ injury in a murine model of septic peritonitis. PLoS One 8:e62792|
|Kharasch, Evan D; Coopersmith, Craig M (2013) Sleeping to survive?: The impact of volatile anesthetics on mortality in sepsis. Anesthesiology 119:755-6|
|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|
|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|
|Dominguez, Jessica A; Vithayathil, Paul J; Khailova, Ludmila et al. (2011) Epidermal growth factor improves survival and prevents intestinal injury in a murine model of pseudomonas aeruginosa pneumonia. Shock 36:381-9|
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