.) Sepsis and the related Systemic Inflammatory Response Syndrome (SIRS) and Multiple Organ Dysfunction Syndrome (MODS) are important causes of death and disability in surgical or injured patients, although the exact cause of death is often obscure. These disorders are complex, involve a number of molecular mediators and effect most organs. Little is understood, however, about the manner in which organ dysfunction develops in these diseases. One important organ that is damaged in sepsis/SIRS/MODS is the lever. Intra-abdominal fecal contamination causes SIRS/MODS-like abnormalities in the liver of rodents. In this study we will examine one proposed mechanism that we believe contributes to the development of liver dysfunction in sepsis /SIRS/MODS. We have shown that intra-abdominal fecal contamination causes an early down regulation of transcription in this organ. This change affects many genes, including some encoding molecules that 1) transfer bile acids out of liver cells and into the biliary system and 2) allow liver cells to burn fat. We propose that the inflammatory cytokine IL-6 mediates some aspects of decreased gene expression, leading to liver cells that cannot excrete bile salts or burn fat. A build-up of bile salts and fat in liver cells """"""""poisons"""""""" them so that they die. When enough liver cells die, liver dysfunction develops. The role played by IL-6 in this proposed mechanism of hepatic dysfunction will be studied in the setting of normal IL-6 levels, IL-6 absence, IL-6 excess and IL-6 repletion after depletion. Several specific measures will be studied. These include 1) transcription of the bile acid transporters Ntcp and Mrp2 and the rate-limiting enzyme in fat oxidation, CPTII, to be determined using transcription elongation analysis, 2) activation of two hepatic nuclear proteins, C/EBPalpha and HNF-1alpha, that modulate transcription of Ntcp, Mrp2 and CPTII and 3) the development of cholestasis (bile trapping in cells) and steatosis (fat trapping in cells) as indicated by microscopic examination of fixed liver sections. In addition, we will mimic IL-6 levels in sepsis in normal mice by 1) administering intravenous IL-6 and 2) injecting a virus that is taken up by the liver and produces high intrahepatic levels of IL-6. We will then study transcription, transcription factor activation, cholestasis and steatosis. These studies should provide key information on the role played by an important inflammatory mediator, IL-6, in the complex series of events that results in the hepatic dysfunction of SIRS/MODS.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM059930-01A1
Application #
6131852
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2000-06-01
Project End
2005-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
1
Fiscal Year
2000
Total Cost
$253,600
Indirect Cost
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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