Thymosin β4 Exerts a Cytoprotective Function and Attenuates Liver Injury in Murine Hepatic Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation

Abstract

Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening complication that may occur after hematopoietic stem cell transplantation (HSCT). Hepatic sinusoidal endothelial cell (HSEC) injury and liver fibrosis are key mechanisms of HSOS. Thymosin β4 (Tβ4) is an active polypeptide that functions in a variety of pathologic and physiologic states, including inflammation regulation, anti-apoptosis, and anti-fibrosis. In this study, we found that Tβ4 can stimulate HSEC proliferation, migration, and tube formation in vitro via activation of pro-survival signaling AKT (protein kinase B). In addition, Tβ4 resisted γ irradiation-induced HSEC growth arrest and apoptosis in parallel with upregulation of anti-apoptotic protein B cell lymphoma extra-large (Bcl-xL) and B cell lymphoma-2 (Bcl-2), which may be associated with activation of AKT. More importantly, Tβ4 significantly inhibited irradiation-induced pro-inflammatory cytokines in parallel with negative regulation of TLR4/MyD88/NF-κB and MAPK p38. Meanwhile, Tβ4 reduced intracellular reactive oxygen species production and upregulated antioxidants in HSECs. Additionally, Tβ4 inhibited irradiation-induced activation of hepatic stellate cells by downregulating the expression of fibrogenic markers α-SMA, PAI-1, and TGF-β. In a murine HSOS model, levels of circulating alanine aminotransferase, aspartate aminotransferase, total bilirubin, and pro-inflammatory cytokines IL-6, IL-1β, and TNF-α were significantly reduced after administration of Tβ4 peptide; furthermore, Tβ4 treatment successfully ameliorated HSEC injury, inflammatory damage, and fibrosis of the murine liver. Taken together, our findings indicate that Tβ4 stimulates proliferation and angiogenesis of HSECs, exerts a cytoprotective effect, and attenuates liver injury in a murine HSOS model, suggesting that its use may be a potential strategy to prevent and treat HSOS after HSCT.

Keywords: Hepatic fibrosis; Hepatic sinusoidal endothelial cells; Hepatic sinusoidal obstruction syndrome; Inflammation; Thymosin β4.