Hyperoxia accelerates progression of hepatic fibrosis by up-regulation of transforming growth factor-β expression

Abstract

To investigate the effect of hypoxia or hyperoxia on the progression of hepatic fibrosis and to examine the role of transforming growth factor-β (TGF-β) in the livers of rats exposed to hypoxic or hyperoxic conditions. Male Sprague-Dawley rats were injected intraperitoneally with thioacetamide to induce hepatic fibrosis and were randomly divided into a hypoxia group, a hyperoxia group and an untreated control group. Ten rats in the hypoxia group were exposed to an altitude of 20000 ft for 1 h/d during 7 wk. Ten rats in the hyperoxia group were exposed to a water depth of 20 m with 100% oxygen supply for 1 h/d during 7 wk. We evaluated the degree of hepatic fibrosis using Masson trichrome stain and examined the expression level of hepatic TGF-β mRNA using quantitative real-time reverse transcriptase-polymerase chain reaction analysis. Eight of 10 rats exposed to hypoxia showed diffuse and confluent fibrosis with the formation of structurally abnormal parenchymal nodules involving the entire liver, consistent with hepatic cirrhosis. Nine of 10 rats exposed to hyperoxia also demonstrated obvious histological findings of hepatic cirrhosis identical to those in hypoxic rat livers. In contrast, 8 of 10 untreated rats had periportal or septal fibrosis only. The frequency of hepatic cirrhosis in hypoxic rats (P = 0.009) and hyperoxic rats (P = 0.003) was significantly higher than that in untreated rats. In addition, hepatic TGF-β mRNA levels in hyperoxic rats were significantly higher than those in untreated rats. The mean value of the normalized TGF-β mRNA/β-actin expression ratio in the hyperoxic rats was 1.9-fold higher than that in the untreated rats (P = 0.027). We demonstrated that both hypoxia and hyperoxia accelerated the progression of hepatic fibrosis in rats. Significant up-regulation of hepatic TGF-β in hyperoxic rats suggests that TGF-β is involved in the acceleration of hepatic fibrosis under hyperoxic conditions.