title: Nature and Implications of Oxidative and Nitrosative Stresses in Autoimmune Hepatitis.
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.
authors.affiliation: Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN, 55905, USA. czaja.albert@mayo.edu.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Czaja
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000276:immunology; D005978:Glutathione / Q000276:immunology / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D050983:NF-E2 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015538:Nitrosation; D018384:Oxidative Stress / Q000276:immunology*; D011499:Protein Processing, Post-Translational / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000276:immunology / Q000378:metabolism; D013879:Thioredoxins / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D056811:Unfolded Protein Response / Q000276:immunology
chemical_list: D000975:Antioxidants; D050983:NF-E2 Transcription Factor; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D013879:Thioredoxins; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione
keywords: Autoimmune hepatitis; Interventions; Nitrosative stress; Oxidative stress