Nitric oxide and redox regulation in the liver: Part I. General considerations and redox biology in hepatitis

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are created in normal hepatocytes and are critical for normal physiologic processes, including oxidative respiration, growth, regeneration, apoptosis, and microsomal defense. When the levels of oxidation products exceed the capacity of normal antioxidant systems, oxidative stress occurs. This type of stress, in the form of ROS and RNS, can be damaging to all liver cells, including hepatocytes, Kupffer cells, stellate cells, and endothelial cells, through induction of inflammation, ischemia, fibrosis, necrosis, apoptosis, or through malignant transformation by damaging lipids, proteins, and/or DNA. In Part I of this review, we will discuss basic redox biology in the liver, including a review of ROS, RNS, and antioxidants, with a focus on nitric oxide as a common source of RNS. We will then review the evidence for oxidative stress as a mechanism of liver injury in hepatitis (alcoholic, viral, nonalcoholic). In Part II of this review, we will review oxidative stress in common pathophysiologic conditions, including ischemia/reperfusion injury, fibrosis, hepatocellular carcinoma, iron overload, Wilson's disease, sepsis, and acetaminophen overdose. Finally, biomarkers, proteomic, and antioxidant therapies will be discussed as areas for future therapeutic interventions.

Figure 1

Reactive oxygen species (ROS) are involved in the oxidation of proteins, lipids, and nucleic acids. Reprinted by permission from dir.nhlbi.nih.gov/labs/lb/es/index.asp. [147]

Figure 2

Pathway for formation of reactive oxygen species. (ROS) Reprinted by permission from Cesaratto L, Vascotto C, Calligaris S, Tell G. The importance of redox state in liver damage. Ann Hepatol. 3:86–92,2004. [23]

Figure 3

The formation of nitric oxide. Reprinted by permission from Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS. Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol. 6:150–166,2005. [60]

Figure 4

Important promoter, inhibitor, and effects of iNOS in the liver. iNOS is expressed hepatocytes, Kupffer cells, vascular endothelial cells, and stellate/Ito cells in the liver. The level of iNOS activity is determined by a variety of stimuli. Based on the amount and duration of activity iNOS can be either protective or toxic.

Figure 5

Critical components in the formation of nitric oxide by eNOS and its role in hepatocytes.

Figure 6

Mechanism of alcohol-induced liver injury. Alcohol metabolism causes acetaldehyde and reactive oxygen species to be generated, both of which can activate stellate cells. ROS/RNS from Kupffer cells can also active stellate cells causing increasing collagen deposition and eventual fibrosis. Reprinted by permission from Halliwell B, JMC G. Free Radicals in Biology and Medicine. 4th ed. oxford: Oxford University Press; 2007. [59]

Figure 7

In non-alcoholic fatty liver disease, the oxidation of free fatty acids increases the production of reactive oxygen species, which, in turn, release cytokines and chemokines, thus causing more inflammation. There is also activation of NF-κB and TNF-α, which again leads to further inflammation. Reprinted by permission from Perlemuter G, Bigorgne A, Cassard-Doulcier AM, Naveau S. Nonalcoholic fatty liver disease: from pathogenesis to patient care. Nat Clin Pract Endocrinol Metab. 3:458–469,2007. [132]