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Inducible nitric oxide synthase in the liver: regulation and function
B S Taylor1, L H Alarcon, T R Billiar
1Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA. BSTA@med.pitt.edu
Biochemistry. Biokhimiia
|August 29, 1998
Summary
Inducible nitric oxide synthase (iNOS) in liver cells protects against injury during sepsis and shock. This adaptive response minimizes inflammation and damage, highlighting nitric oxide's (NO) crucial role in liver health.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Hepatocytes express inducible nitric oxide synthase (iNOS) under various physiological and pathophysiological conditions, including septic and hemorrhagic shock.
- The molecular regulation of iNOS expression is intricate, involving multiple gene expression levels and transcription factors like NF-kappaB.
- Cytokines such as TNF-alpha, IL-1beta, and INF-gamma synergistically activate iNOS expression in the liver.
Purpose of the Study:
- To investigate the role and regulation of inducible nitric oxide synthase (iNOS) in liver function and injury.
- To elucidate the protective mechanisms of nitric oxide (NO) in the liver during conditions like sepsis and ischemia reperfusion.
- To understand the adaptive response of hepatic iNOS expression in minimizing inflammatory injury.
Main Methods:
- Cloning of the human iNOS gene from cytokine-stimulated hepatocytes.
- Investigating the regulation of iNOS expression by various factors including transcription factors, cytokines, steroids, and NO itself.
- Utilizing rodent models of endotoxemia to study the effects of iNOS inhibition on hepatic damage.
Main Results:
- Hepatic iNOS induction is differentially regulated and not a mandatory component of the acute phase response.
- Induced nitric oxide (NO) synthesis plays a vital role in hepatocyte function and liver protection during sepsis and ischemia reperfusion.
- Nonspecific NOS inhibitors significantly increased hepatic damage in a rodent model of endotoxemia, underscoring NO's protective role.
Conclusions:
- Nitric oxide (NO) exerts cytoprotective effects in the liver by preventing intravascular thrombosis, neutralizing radicals, and inhibiting apoptosis.
- Hepatic iNOS expression functions as an adaptive response to mitigate inflammatory injury and protect the liver.
- NO has diverse roles in the liver, including anti-tumor and antimicrobial effects, and is implicated in cirrhosis-related vasodilation.