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Nature and Implications of Oxidative and Nitrosative Stresses in Autoimmune Hepatitis

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Abstract

Oxidative and nitrosative stresses can damage cellular membranes, disrupt mitochondrial function, alter gene expression, promote the apoptosis and necrosis of hepatocytes, and increase fibrosis in diverse acute and chronic liver diseases, including autoimmune hepatitis. The objectives of this review are to describe the mechanisms of oxidative and nitrosative stresses in inflammatory liver disease, indicate the pathogenic implications of these stresses in autoimmune hepatitis, and suggest investigational opportunities to develop interventions that counter them. The principal antioxidant defenses, including glutathione production, the activities of antioxidant enzymes, and the release of the nuclear factor erythroid 2-related factor 2, may be inadequate or suppressed by transforming growth factor beta. The generation of reactive oxygen species can intensify nitrosative stress, and this stress may not be adequately modulated by the thioredoxin–thioredoxin reductase system and induce post-translational modifications of proteins that further disrupt hepatocyte function. The unfolded protein response and autophagy may be unable to restore redox stability, meet metabolic demands, and maintain hepatocyte survival. Emerging interventions with highly selective site- and organelle-specific actions may improve outcomes, and they include inhibitors of nicotinamide adenine dinucleotide phosphate oxidase, nitric oxide synthase, and transforming growth factor beta. Pharmacological manipulation of nuclear transcription factors may favor expression of antioxidant genes, and stimulation of chaperone proteins within the endoplasmic reticulum and modulation of autophagy may prevent hepatic fibrosis and enhance cell survival. These interventions constitute investigational opportunities to improve the management of autoimmune hepatitis.

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Author contribution

Albert J. Czaja, MD researched, designed, and wrote this article. The tables are original, constructed by Dr. Czaja, fully referenced, and developed solely for this review.

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  1. Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA

    Albert J. Czaja

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Correspondence to Albert J. Czaja.

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This review did not receive financial support from a funding agency or institution, and Albert J. Czaja, MD has no conflict of interests to declare.

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Czaja, A.J. Nature and Implications of Oxidative and Nitrosative Stresses in Autoimmune Hepatitis. Dig Dis Sci 61, 2784–2803 (2016). https://doi.org/10.1007/s10620-016-4247-6

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  • DOI: https://doi.org/10.1007/s10620-016-4247-6

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