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Project: Immunomodulation of Sepsis in Biliary Obstruction

Investigators: Rebecca M. Minter at University of Michigan. Created at: 2007-01-03 11:14. Last updated at: 2007-02-15 16:02.

Grant support: NIH NIGMS K08 GM074678-01A1.


Sepsis and the development of multi-system organ failure remain major causes of death in patients with underlying liver disease, particularly following surgical intervention. Despite significant advances in operative technique, critical care medicine, and antimicrobial therapy, there has been little improvement in the outcome of these patients. Though several studies have pointed to an altered immune response to infectious stimuli in the setting of liver disease, the exact nature of this response is yet to be defined. There are numerous reports of a hyper-inflammatory response following infection in both humans and rodents with biliary obstruction, however there is also evidence of an increase in anti-inflammatory cytokines in these same patients and animals. We hypothesize that the dysregulated immune response observed in the setting of biliary obstruction to infectious stimuli is marked by a dynamic fluctuation between a pro-and anti-inflammatory state.

Therefore, the purpose of the present studies is to define the exact nature of the inflammatory response to Gram-negative infection in animals with biliary obstruction, and to determine if parameters which are predictive of a deleterious outcome can be identified and potentially modulated, thus leading to decreased organ injury and death. Dynamic Bayesian Analysis is being utilized in these studies to identify causal or apparently causal relationships between specific clinical or biochemical parameters and/or inflammatory mediators and the development of sepsis, organ injury and death, thus identifying potential targets for immunomodulation. Ultimately, the results of these studies will provide insight into the immune response to infectious stimuli in the setting of cholestatic liver disease. Until this response is well understood, it will be difficult to develop effective strategies for the treatment and prevention of septic complications in these patients.

This work is being directed by principal investigator, Dr. Rebecca M. Minter in the Department of Surgery, with the assistance of Dr. Xiaoming Bi. Support for this work is provided by the National Institutes of Health (NIH NIGMS K08 GM074678-01A1), the Society of University Surgeons Foundation, and the University of Michigan Department of Surgery.

Status: Approved


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