Profound changes in liver function accompany the host's response to severe infections (sepsis) or trauma. These responses can be physiologic, as in the acute phase response, or pathologic, as in the often-fatal liver failure associated with multiple organ failure. Even though the external signals (IL-6, IL-1, TNF) inducing the acute phase response are known, the intracellular second messengers and regulating process are not understood. Also unknown is the cause of the metabolic defect in hepatocytes which induce the liver failure associated with the organ failure syndrome. Work by the principal investigator has shown that liver cells (Kupffer cells and hepatocytes) exposed to septic stimuli produce significant quantities of nitric oxide, a highly reactive compound derived from L-arginine. Based on the known biologic functions of authentic nitric oxide in other systems and cell types, it is hypothesized in this proposal that hepatocyte-derived nitric oxide contributes to both the physiologic and pathologic responses of liver cells in sepsis. By activating enzymes involved in internal signal transduction, such as guanylate cyclase or ADP-ribosyltransferase, nitric oxide might play a role in regulating intracellular processes during the acute phase response. Nitric oxide released by liver cells into the extracellular space might protect the hepatocytes from adjacent activated Kupffer cells or infiltrating inflammatory cells by inhibiting cellular responses or detoxifying oxygen radicals. Through its action as a platelet disaggregating agent, hepatocyte-derived nitric oxide might function to prevent intrahepatic thrombosis. Larger quantities of nitric oxide can inactivate specific mitochondrial enzymes; therefore, excessive or prolonged nitric oxide production might have pathologic consequences by interfering with hepatocyte mitochondrial respiration. All of these possibilities will be thoroughly tested using cultured hepatocytes induced to synthesize nitric oxide endogenously or hepatocytes exposed to exogenous nitric oxide. To correlate in vitro and in vivo responses, hepatocytes will be stimulated to produce nitric oxide in vitro by exposing animals to inflammatory stimuli. Studies on hepatocytes isolated from these animals will seek to demonstrate the effects of in vivo nitric oxide production on hepatocytes. In addition the kinetics and specific signals of in vitro and in vivo hepatocyte nitric oxide production will be completely characterized.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM044100-05
Application #
2182373
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Pribis, John P; Al-Abed, Yousef; Yang, Huan et al. (2015) The HIV Protease Inhibitor Saquinavir Inhibits HMGB1-Driven Inflammation by Targeting the Interaction of Cathepsin V with TLR4/MyD88. Mol Med 21:749-757
Sengupta, Rajib; Billiar, Timothy R; Atkins, James L et al. (2009) Nitric oxide and dihydrolipoic acid modulate the activity of caspase 3 in HepG2 cells. FEBS Lett 583:3525-30
Billiar, T R (1995) Nitric oxide. Novel biology with clinical relevance. Ann Surg 221:339-49