4-hydroxy-2-nonenal and Hepatitis

While most of the investigations into the causative events in the development of alcoholic liver disease (ALD) have been focused on multiple factors, increasing interest has centered around the possible role of immune mechanisms in the pathogenesis and perpetuation of ALD. This is because many of the clinical features of ALD suggest that immune effector mechanisms may be contributing to liver tissue damage, as evidenced by the detection of circulating autoantibodies, and the presence of CD4+ and CD8+ lymphoid cells in the livers of patients with ALD. One mechanism that has been associated with the development of autoimmune responses is the modification (haptenation or adduction) of liver proteins with aldehydes or other products of oxidative stress. This is because it has been shown that these adducted proteins can induce specific immune responses, to the adduct, the adduct plus protein (conformational antigens), as well as the unmodified parts of the protein. More importantly, it is possible to demonstrate that adducted self-proteins can induce reactivity to the normal self-protein and thereby induce autoimmune responses. Therefore, it is the purpose of this manuscript to outline the mechanism(s) by which these modified self proteins can induce autoimmune reactivity, and thus play a role in the development and/or progression of ALD.

Topics: Acetaldehyde; Aldehydes; Animals; Apoptosis; Autoimmune Diseases; Autoimmunity; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death; Disease Progression; Haptens; Hepatitis; Humans; Immune System; Lipoproteins, LDL; Liver; Liver Diseases, Alcoholic; Malondialdehyde; Necrosis; Oxidative Stress; Receptors, Scavenger; Self Tolerance

Viral hepatitis resulting in chronic liver disease is an important clinical challenge and insight into the cellular processes that drive pathogenesis will be critical in order to develop new diagnostic and therapeutic options. Nuclear inclusions in viral and non-viral hepatitis are well documented and have diagnostic significance in some disease contexts. However, the origins and functional consequences of these nuclear inclusions remain elusive. To date the clinical observation of nuclear inclusions in viral and non-viral hepatitis has not been explored at depth in murine models of liver disease. Herein, we report that in a transgenic model of hepatitis B surface antigen mediated hepatitis, murine hepatocytes exhibit nuclear inclusions. Cells bearing nuclear inclusions were more likely to express markers of cell proliferation. We also established a correlation between these inclusions and oxidative stress. N-acetyl cysteine treatment effectively reduced oxidative stress levels, relieved endoplasmic reticulum (ER) stress, and the number of nuclear inclusions we observed in the transgenic mice. Our results suggest that the presence of nuclear inclusions in hepatocytes correlates with oxidative stress and cellular proliferation in a model of antigen mediated hepatitis.

Topics: Aldehydes; Animals; Biomarkers; Cell Death; Cell Nucleus; Cell Nucleus Size; Cellular Senescence; Disease Models, Animal; Endoplasmic Reticulum; Glycogen; Hepatitis; Hepatitis B Surface Antigens; Hepatocytes; Intranuclear Inclusion Bodies; Mice, Inbred C57BL; Mice, Transgenic; Oxidative Stress; Proliferating Cell Nuclear Antigen; Vacuoles

Increased hepatic sympathetic activity affects hepatic metabolism and hemodynamics and subsequently causes acute hepatic injury. We examined whether the vesicovascular reflex evoked by bladder overdistension could affect hepatic function, specifically reactive oxygen species (ROS)-induced inflammation and apoptosis, through activation of the hepatic sympathetic nerve. We evaluated the hepatic hemodynamics, hepatic sympathetic nervous activities, and cystometrograms in anesthetized rats subjected to acute urinary retention. We used a chemiluminescence method, an in situ nitro blue tetrazolium perfusion technique, and a DNA fragmentation/apoptosis-related protein assay to demonstrate de novo and colocalize superoxide production and apoptosis formation in rat liver. Acute urinary retention increased the hepatic sympathetic-dependent vesicovascular reflex, which caused hepatic vasoconstriction/hypoxia and increased superoxide anion production from the periportal Kupffer cells and hepatocytes, which were aggravated by the increase in volume and duration of urinary retention. The ROS-enhanced proinflammatory NF-kappaB, activator protein-1, and ICAM-1 expression also promoted proapoptotic mechanisms, including increases in the Bax/Bcl-2 ratio, CPP32 expression, poly-(ADP-ribose)-polymerase cleavages, and DNA fragmentation and apoptotic cells in the liver. The proinflammatory and proapoptotic mechanisms were significantly attenuated in rats treated with hepatic sympathetic nerve denervation or catechin (antioxidant) supplement. In conclusion, our results suggest that acute urine retention enhances hepatic sympathetic activity, which causes hepatic vasoconstriction and evokes proinflammatory and proapoptotic oxidative injury in the rat liver. Reduction of the hepatic sympathetic tone or antioxidant supplement significantly attenuates these injuries.

Topics: Acute Disease; Aldehydes; Animals; Bile; DNA Fragmentation; Female; Gene Expression; Hepatitis; Intercellular Adhesion Molecule-1; Liver; Nitroblue Tetrazolium; Rats; Rats, Wistar; Reactive Oxygen Species; Reflex; Staining and Labeling; Sympathetic Nervous System; Urinary Bladder; Urinary Retention