Acute liver failure is a devastating clinical condition with a high mortality rate. This affects patients with and without prior liver disease. Inability of hepatocytes to regenerate and their progressive death leads to acute liver failure. The mechanisms of hepatocyte depletion in acute liver failure are inadequately understood, precluding effective pharmacological therapy. However, endotoxemia is always associated with acute liver failure and is a major contributor of catastrophic failure. In the United States alone more than 20,000 people die of septic shock and evidence indicates that hepatic stellate cells inevitably play a major role in response to endotoxemia. The normally quiescent stellate cells regulate liver blood flow by contractility and maintain its architecture by producing components of extracellular matrix. During chronic liver injury, stellate cells transform into proliferating, highly contractile and fibrogenic myofibroblast cells. Endotoxin causes upregulation of the endothelin system in stellate cells and the consequent profound hepatic vasoconstriction contributes to endotoxin-induced liver injury. Moreover, endotoxin-conditioned media of quiescent and activated stellate cells strongly inhibit DNA synthesis in hepatocytes. Endotoxin increases the expression of nitric oxide, IL-1-beta, IL-6, but not of TGF-beta or TNF-alpha in both phenotypes. However, none of these potent mediators is responsible for the inhibition of hepatocyte DNA synthesis. Also, stellate cells in the presence of endotoxin and reactive oxygen species release factors which kill hepatocytes. Reactive oxygen species are generated by the resident macrophages (Kupffer cells) in response to endotoxin. These observations strongly suggest the synthesis of one or more as yet unidentified mediators which promote liver failure.
The specific aims of this proposal are: 1) to determine the cellular mechanisms by which stellate cells respond to endotoxin, 2) to determine the mechanisms by which stellate cells plus endotoxin- or stellate cells plus reactive oxygen species-conditioned media cause injury to hepatocytes, 3) to determine the effects and mechanisms of endotoxin treatment of normal and cirrhotic rats on stellate cell-mediated hepatocyte injury, and 4) to identify and characterize the mediators of hepatocyte injury produced by stellate cells. The outcome of this investigation will provide profound insights into the central regulatory role of stellate cells in liver pathophysiology. Importantly, identification of the stellate cell-derived mediators will provide a rational basis for the therapy of life-threatening liver failure and other liver disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054411-08
Application #
6943411
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Doo, Edward
Project Start
1998-09-25
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
8
Fiscal Year
2005
Total Cost
$259,041
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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