Thymosin beta 4 Prevents Oxidative Stress, Inflammation, and Fibrosis in Ethanol- and LPS-Induced Liver Injury in Mice

Thymosin beta 4 (T beta 4), an actin-sequestering protein, is involved in tissue development and regeneration. It prevents inflammation and fibrosis in several tissues. We investigated the role of T beta 4 in chronic ethanol- and acute lipopolysaccharide(LPS-) induced mouse liver injury. C57BL/6 mice were fed 5% ethanol in liquid diet for 4 weeks plus binge ethanol (5 g/kg, gavage) with or without LPS (2 mg/kg, intraperitoneal) for 6 hours. T beta 4 (1 mg/kg, intraperitoneal) was administered for I week. We demonstrated that T beta 4 prevented ethanol- and LPS-mediated increase in liver injury markers as well as changes in liver pathology. It also prevented ethanol- and LPS-mediated increase in oxidative stress by decreasing ROS and lipid peroxidation and increasing the antioxidants, reduced glutathione and manganese-dependent superoxide dismutase. It also prevented the activation of nuclear factor kappa B by blocking the phosphorylation of the inhibitory protein, I kappa B, thereby prevented proinflammatory cytokine production. Moreover, T beta 4 prevented fibrogenesis by suppressing the epigenetic repressor, methylCpG-binding protein 2, that coordinately reversed the expression of peroxisome proliferator-activated receptor-gamma and downregulated fibrogenic genes, platelet-derived growth factor-beta receptor, alpha-smooth muscle actin, collagen 1, and fibronectin, resulting in reduced fibrosis. Our data suggest that T beta 4 has antioxidant, anti-inflammatory, and antifibrotic potential during alcoholic liver injury.