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World J Gastroenterol. May 21, 2014; 20(19): 5746-5759
Published online May 21, 2014. doi: 10.3748/wjg.v20.i19.5746
Pathogenic role of oxidative and nitrosative stress in primary biliary cirrhosis
Ignazio Grattagliano, Giuseppe Calamita, Tiziana Cocco, David Q-H Wang, Piero Portincasa
Ignazio Grattagliano, Italian College of General Practitioners, 50100 Florence, Bari 70124, Italy
Giuseppe Calamita, Department of Bioscience, Biotechnology, and Biopharmaceutics, “Aldo Moro” University Medical School, Bari 70124, Italy
Tiziana Cocco, Department of Basic Medical Science, Neurosciences, and Sense Organs, “Aldo Moro” University Medical School, Bari 70124, Italy
David Q-H Wang, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO 63104, United States
Piero Portincasa, Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University Medical School, Bari 70124, Italy
Author contributions: Grattagliano I designed and wrote the article; Calamita G wrote the aquaporin section; Cocco T revised the paragraph on mitochondria; Wang DQH revised the language; Wang DQH, Portincasa P wrote the section on the intestine and supervised the article.
Correspondence to: Ignazio Grattagliano, MD, Italian College of General Practitioners, Bari, Pzza G Cesare, 11, 50100 Florence, 70124 Bari, Italy. i.grattagliano@semeiotica.uniba.it
Telephone: +39-80-5478233 Fax: +39-80-5478232
Received: October 2, 2013
Revised: January 18, 2014
Accepted: March 7, 2014
Published online: May 21, 2014
Processing time: 227 Days and 21.4 Hours
Abstract

Primary biliary cirrhosis is a multifactor autoimmune disease characterized by hepatic and systemic manifestations, with immune system dysregulation and abnormalities in the hepatic metabolism of bile salts, lipids, and nutrients, as well as destruction of membrane lipids and mitochondrial dysfunction. Both oxidative and nitrosative stress are associated with ongoing manifestations of the disease. In particular, abnormalities in nitric oxide metabolism and thiol oxidation already occur at early stages, thus leading to the hypothesis that these biochemical events play a pathogenic role in primary biliary cirrhosis. Moreover, the association of these metabolic abnormalities with the progression of the disease may indicate some biochemical parameters as early diagnostic markers of disease evolution, and may open up the potential for pharmacological intervention to inhibit intra- and extra-cellular stress events for resuming hepatocellular functions. The following paragraphs summarize the current knowledge by outlining molecular mechanisms of the disease related to these stress events.

Keywords: Aquaporins; Bile salts; Chronic cholestasis; Glutathione; Mitochondria; Nitrosothiols; Nitrotyrosine; Protein sulfhydryls; Thioredoxin

Core tip: Both oxidative and nitrosative stress are associated with ongoing manifestations of chronic cholestasis, and in particular, primary biliary cirrhosis. Abnormalities in nitric oxide metabolism and thiols oxidation already occur at early stages, thus leading to the hypothesis that these biochemical events play a pathogenic role in primary biliary cirrhosis. The association of these metabolic abnormalities with the progression of the disease may indicate some biochemical parameters as early diagnostic markers of disease evolution, and may open up the potential for pharmacological intervention to inhibit intra- and extra-cellular stress events for resuming hepatocellular functions. This article summarizes the current knowledge by outlining molecular mechanisms of the disease related to these stress events.