Mechanisms Research Of Antifibrotic Effects Of Gambogic Acid

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disorder with poor prognosis.The treatment options for IPF are very limited. Gambogic acid (GA) has anticancer effect and anti-proliferative activity which is extracted from a dried yellow resin of the Garcinia hanburyiHook.f. [Clusiaceae (Guttiferae)] in Southeast Asia. However, the anti-fibrotic activities of GA have not been previously investigated.Methods: In this study, the effects of GA on TGF-?1-mediated epithelial-mesenchymal transition(EMT) in A549 cells and endothelial-mesenchymal transition (EndoMT) in human pulmonary microvascular endothelial cells ( HPMECs ) , on the proliferation of human lung fibroblasts(HLF-1) were investigated in vitro, and on bleomycin (BLM) -induced pulmonary fibrosis was investigated in vivo.Results: In TGF-?1 stimulated A549 cells,treatment with GA resulted in a reduction of EMT with a decrease in vimentin and p-Smad3 and an increase in E-cadherin instead. In TGF-?1 stimulated HPMECs, treatment with GA resulted in a reduction of EndoMT with a decrease in vimentin, and an increase in VE-cadherin instead. In the hypoxic HPMECs, treatment with GA reduced Vasohibin-2(VASH-2) , whereas increased VASH-1. In TGF-?1 stimulated HLF-1, treatment with GA reduced HLF-1 proliferation with a decrease in platelet-derived growth factor (PDGF ) and fibroblast growth factor (FGF-2 ) expressions. In vivo, treatment with GA for 2 weeks resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with a lower VASH-2. Instead, it was observed a higher VASH-1 expression at early stage of fibrosis at 1 mg/kg, with reductions of the pathological score,collagen deposition, a-SMA,PDGF and FGF-2 expressions at fibrotic stage at 0.5 mg/kg and 1 mg/kg.Conclusion : In summary, GA reversed EMT and EndoMT, as well as HLF-1 proliferation in vitro and prevented pulmonary fibrosis in vivo by modulating VASH-2/VASH-1 and suppressing the TGF-?1/Smad3 pathway.