The Role Of Hypoxia In Formation Of Hepatic Fibrosis In Bdl Rats

Fibrosis is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although the mechanisms is very complex,liver becomes hypoxic may be the main promotion factors in during early stages of this desease.AimTo study the role of hypoxia in BDL induced hepatic fibrosis in rats.Methods1.BDL or sham-operations were performed, and rats were sacrificed at postoperative 1d,3d,7d,14d,21d,28d, respectively. Then the histopathological and ultrastructural changes were observed. TGF-β1 and collagen I mRNA expressions in the whole liver were assayed by RT-PCR, and the HIF-1αprotein andα-SMA expression were assayed by Western blot.2.Upon hypoxia, the expression of HIF-1α,TGF-β1 and collagen I mRNA in rat HSCs HSC-T6 were assayed by RT-PCR, and theα-SMA protein expression was assayed by Western blot. Upon hypoxia or normoxia, the expression of collagen I mRNA was assayed by RT-PCR after cell culture was supplemented with neutralizing anti-TGF-β1 antibody,CoCl2 or 2ME2.Results1. Electron microscopy shows that hypoxia and energy metabolism dysfunction appeared in the livers of rat during the early stage following surgery ; HIF-1αprotein was increased 3 days after surgery, and TGF-β1,collage I mRNA was increased after 7 days;2. Hypoxia elevated expression of HIF-1α,TGF-β1,collagen I mRNA andα-SMA protein in HSC-T6; In normoxia,CoCl2 could induce the expression of collagen I mRNA, in opposite, the neutralizing anti-TGF-β1 antibody and2ME2 could inhibit the expression of collagen I mRNA upon hypoxia.ConclusionHypoxia induced TGF-β1 expression and directly activate HSC via TGF-β1-dependent signaling pathway. Meanwhile, TGF-β1 and HIF-1αmay synergically increased production of collagen I. Therefore, hypoxia may play an important role in the development of cholestasis-induced liver fibrosis.