Thymosin β4 Prevents Oxidative Stress, Inflammation, and Fibrosis in Ethanol- and LPS-Induced Liver Injury in Mice

Abstract

Thymosin beta 4 (Tβ4), an actin-sequestering protein, is involved in tissue development and regeneration. It prevents inflammation and fibrosis in several tissues. We investigated the role of Tβ4 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. Tβ4 (1 mg/kg, intraperitoneal) was administered for 1 week. We demonstrated that Tβ4 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, IκB, thereby prevented proinflammatory cytokine production. Moreover, Tβ4 prevented fibrogenesis by suppressing the epigenetic repressor, methyl-CpG-binding protein 2, that coordinately reversed the expression of peroxisome proliferator-activated receptor-γ and downregulated fibrogenic genes, platelet-derived growth factor-β receptor, α-smooth muscle actin, collagen 1, and fibronectin, resulting in reduced fibrosis. Our data suggest that Tβ4 has antioxidant, anti-inflammatory, and antifibrotic potential during alcoholic liver injury.

S‐allyl cysteine, an active ingredient of garlic, attenuates acute liver dysfunction induced by lipopolysaccharide/d‐galactosamine in mouse: Underlying mechanisms

“…[27] Inappropriate inflammatory reactions are also key players in liver injury subsequent to exposure to toxic agents. [8,58] LPS can mobilize hepatic Kupffer cells with excess production and release of proinflammatory cytokines. Accordingly, mitigation of inflammatory reactions is a suggested strategy for the therapy of ALI conditions.…”

Anti‑inflammatory effects of glycine thymosin�β4 eye drops in experimental dry eye

“…Previous studies have reported that Tβ4 regulated the inflammatory process by reducing the production of inflammatory cytokines and chemokines in acute myocardial infarction, alcoholic liver disease and neurodegenerative diseases (17,(26)(27)(28). In ophthalmology, several studies have reported that topical Tβ4 application improved clinical dry eye parameters, including tear volume, TBUT and corneal staining scores in human and experimental DED (18,19).…”

Thymosin β4: potential to treat epidermolysis bullosa and other severe dermal injuries

“…A reduction in scar tissue has been observed by multiple research groups in different animal models of injury, including excisional wounds, myocardial infarct, stroke, and fibrosis of the lung, liver, and kidney [44][45][46][47][48][49][50][51] (table 2). Thymosin ␤4 reduces oxidative stress by targeting anti-oxidative genes [52][53][54][55][56][57]. It reduced toxicity by inhibiting inducible nitric oxide synthetase (iNOS) and cyclooxygenase-2, resulting in decreased reactive oxygen species (ROS), decreased secretion of NO, and decreased prostaglandins.…”

“…The migration activity of thymosin ␤4 is, in part, mediated by its binding to actin. Thymosin ␤4 binds to actin, and the actin binding domain has been identified as the site responsible for cell migration [57]. Thymosin ␤4 coordinates actin polymerization with metalloproteinase synthesis to promote cell migration.…”