Busulfan-induced hepatic sinusoidal endothelial cell injury: Modulatory role of pirfenidone for therapeutic purposes

Abstract

Transplantation conditioning using Busulfan has been known to cause hepatotoxicity, which has great individual differences. Some have mild symptoms like the increase of hepatic drug-metabolizing enzyme, while others may have very serious ones, like hepatic sinusoidal obstruction syndrome. However, simply controlling the exposure of Busulfan may not effectively prevent or reduce the occurrence of hepatic sinusoidal obstruction syndrome. The occurrence of hepatic sinusoid obstruction syndrome is closely related to hepatic sinusoidal endothelial cells (HSECs). The objective of this study is to investigate the potential protective effect of Pirfenidone against Busulfan-induced damage to hepatic sinusoidal endothelial cells and to preliminarily explore the mechanisms underlying this protective effect. Our results indicate that Pirfenidone has a great protective effect on the injury induced by Busulfan. In addition, Busulfan increased the relative mRNA expression of transforming growth factor-β1 (TGF-β1), collagen and tissue inhibitor of metalloproteinase-1 in HSECs. After pretreatment with Pirfenidone, the expression level of TGF-β1 was down-regulated. Mechanically, Pirfenidone primarily improves liver fibrosis by inhibiting collagen formation and hepatic stellate cell activation, thereby providing a protective effect on HSECs damaged by Busulfan. Therefore, Pirfenidone may reduce the hepatotoxicity caused by transplantation conditioning regimens based on Busulfan.