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.

Public Health Relevance

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.

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
Emory University
Schools of Medicine
United States
Zip Code
McConnell, Kevin W; Coopersmith, Craig M (2016) Pathophysiology of septic shock: From bench to bedside. Presse Med 45:e93-8
Lyons, John D; Ford, Mandy L; Coopersmith, Craig M (2016) The Microbiome in Critical Illness: Firm Conclusions or Bact to Square One? Dig Dis Sci 61:1420-1
Klingensmith, Nathan J; Yoseph, Benyam P; Liang, Zhe et al. (2016) Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion. Shock :
Liu, Danya; Burd, Eileen M; Coopersmith, Craig M et al. (2016) Retrogenic ICOS Expression Increases Differentiation of KLRG-1hiCD127loCD8+ T Cells during Listeria Infection and Diminishes Recall Responses. J Immunol 196:1000-12
Yoseph, Benyam P; Klingensmith, Nathan J; Liang, Zhe et al. (2016) Mechanisms of Intestinal Barrier Dysfunction in Sepsis. Shock 46:52-9
Klingensmith, Nathan J; Coopersmith, Craig M (2016) The Gut as the Motor of Multiple Organ Dysfunction in Critical Illness. Crit Care Clin 32:203-12
Lyons, John D; Mittal, Rohit; Fay, Katherine T et al. (2016) Murine Lung Cancer Increases CD4+ T Cell Apoptosis and Decreases Gut Proliferative Capacity in Sepsis. PLoS One 11:e0149069
Mittal, Rohit; Chen, Ching-Wen; Lyons, John D et al. (2015) Murine lung cancer induces generalized T-cell exhaustion. J Surg Res 195:541-9
Mittal, Rohit; Coopersmith, Craig M (2014) Redefining the gut as the motor of critical illness. Trends Mol Med 20:214-23
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

Showing the most recent 10 out of 50 publications