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Inhibition of apoptosis protects mice from ethanol-mediated acceleration of early markers of CCl4 -induced fibrosis but not steatosis or inflammation.

ABSTRACT: Correlative evidence indicates that apoptosis is associated with the progression of alcoholic liver disease. If apoptosis contributes to ethanol (EtOH)-induced steatohepatitis and/or fibrosis, then mice deficient in Bid, a key pro-apoptotic Bcl-2 family member, or mice treated with a pan-caspase inhibitor (VX166) should be resistant to EtOH-induced liver injury.This hypothesis was tested in mice using a model of chronic, heavy EtOH-induced liver injury, as well as in a model in which moderate EtOH feeding accelerated the appearance of early markers of hepatic fibrosis in response to acute carbon tetrachloride (CCl(4) ) exposure.Chronic EtOH feeding to mice increased TUNEL- and cytokeratin-18-positive cells in the liver, as well as the expression of receptor-interacting protein kinase 3 (RIP3), a marker of necroptosis. In this model, Bid-/- mice or wild-type mice treated with VX166 were protected from EtOH-induced apoptosis, but not EtOH-induced RIP3 expression. Bid deficiency or inhibition of caspase activity did not protect mice from EtOH-induced increases in plasma alanine and aspartate amino transferase activity, steatosis, or mRNA expression of some inflammatory cytokines. Moderate EtOH feeding to mice enhanced the response of mice to acute CCl(4) exposure, resulting in increased expression of ?-smooth muscle actin and accumulation of extracellular matrix protein. VX166-treatment attenuated EtOH-mediated acceleration of these early indicators of CCl(4) -induced hepatic fibrosis, decreasing the expression of ?-smooth muscle actin, and the accumulation of extracellular matrix protein.EtOH-induced apoptosis of hepatocytes was mediated by Bid. Apoptosis played a critical role in the accelerating the appearance of early markers of CCl(4) -induced fibrosis by moderate EtOH but did not contribute to EtOH-induced hepatocyte injury, steatosis, or expression of mRNA for some inflammatory cytokines.

SUBMITTER: Roychowdhury S

PROVIDER: S-EPMC3337974 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Inhibition of apoptosis protects mice from ethanol-mediated acceleration of early markers of CCl4 -induced fibrosis but not steatosis or inflammation.

Roychowdhury Sanjoy S Chiang Dian J DJ Mandal Palash P McMullen Megan R MR Liu Xiuli X Cohen Jessica I JI Pollard John J Feldstein Ariel E AE Nagy Laura E LE

Alcoholism, clinical and experimental research 20120124 7

<h4>Background</h4>Correlative evidence indicates that apoptosis is associated with the progression of alcoholic liver disease. If apoptosis contributes to ethanol (EtOH)-induced steatohepatitis and/or fibrosis, then mice deficient in Bid, a key pro-apoptotic Bcl-2 family member, or mice treated with a pan-caspase inhibitor (VX166) should be resistant to EtOH-induced liver injury.<h4>Methods</h4>This hypothesis was tested in mice using a model of chronic, heavy EtOH-induced liver injury, as well ...[more]

PMID: 22273278

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Project description:AimsTransient Receptor Potential Melastatin 7 (TRPM7) cation channel is a chanzyme (channel + kinase) that influences cellular Mg2+ homeostasis and vascular signalling. However, the pathophysiological significance of TRPM7 in the cardiovascular system is unclear. The aim of this study was to investigate the role of this chanzyme in the cardiovascular system focusing on inflammation and fibrosis.Methods and resultsTRPM7-deficient mice with deletion of the kinase domain (TRPM7+/?kinase) were studied and molecular mechanisms investigated in TRPM7+/?kinase bone marrow-derived macrophages (BMDM) and co-culture systems with cardiac fibroblasts. TRPM7-deficient mice had significant cardiac hypertrophy, fibrosis, and inflammation. Cardiac collagen and fibronectin content, expression of pro-inflammatory mediators (SMAD3, TGF?) and cytokines [interleukin (IL)-6, IL-10, IL-12, tumour necrosis factor-?] and phosphorylation of the pro-inflammatory signalling molecule Stat1, were increased in TRPM7+/?kinase mice. These processes were associated with infiltration of inflammatory cells (F4/80+CD206+ cardiac macrophages) and increased galectin-3 expression. Cardiac [Mg2+]i, but not [Ca2+]i, was reduced in TRPM7+/?kinase mice. Calpain, a downstream TRPM7 target, was upregulated (increased expression and activation) in TRPM7+/?kinase hearts. Vascular functional and inflammatory responses, assessed in vivo by intra-vital microscopy, demonstrated impaired neutrophil rolling, increased neutrophil: endothelial attachment and transmigration of leucocytes in TRPM7+/?kinase mice. TRPM7+/?kinase BMDMs had increased levels of galectin-3, IL-10, and IL-6. In co-culture systems, TRPM7+/?kinase macrophages increased expression of fibronectin, proliferating cell nuclear antigen, and TGF? in cardiac fibroblasts from wild-type mice, effects ameliorated by MgCl2 treatment.ConclusionsWe identify a novel anti-inflammatory and anti-fibrotic role for TRPM7 and suggest that its protective effects are mediated, in part, through Mg2+-sensitive processes.

Dataset Information

Inhibition of apoptosis protects mice from ethanol-mediated acceleration of early markers of CCl4 -induced fibrosis but not steatosis or inflammation.

Publications

Inhibition of apoptosis protects mice from ethanol-mediated acceleration of early markers of CCl4 -induced fibrosis but not steatosis or inflammation.

Similar Datasets

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