title: Protective role of gambogic acid in experimental pulmonary fibrosis in vitro and in vivo.
abstract: 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 hanburyi Hook.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-β1-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-β1 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-β1 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-β1 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, α-SMA, PDGF and FGF-2 expressions at fibrotic stage at 0.5 mg/kg and 1 mg/kg.
  
  
  CONCLUSIONS
  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-β1/Smad3 pathway.
authors.affiliation: The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai, P.R. China.
authors.forename: Yubei
authors.initials: Y
authors.lastname: Qu
authors.affiliation: The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai, P.R. China.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai, P.R. China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Ji
authors.affiliation: The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai, P.R. China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhua
authors.affiliation: The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai, P.R. China. Electronic address: Lucky_lcj@sina.com.
authors.forename: Changjun
authors.initials: C
authors.lastname: Lv
authors.affiliation: The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai, P.R. China. Electronic address: jwl518@163.com.
authors.forename: Wanglin
authors.initials: W
authors.lastname: Jiang
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D015820:Cadherins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D029760:Garcinia / Q000737:chemistry*; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D042501:Angiogenic Proteins; D015820:Cadherins; D018797:Cell Cycle Proteins; D010936:Plant Extracts; D010982:Platelet-Derived Growth Factor; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D053773:Transforming Growth Factor beta1; C493181:VASH1 protein, human; C574858:VASH2 protein, human; D044004:Xanthones; D016222:Fibroblast Growth Factor 2; D001761:Bleomycin; C052659:gambogic acid; D003094:Collagen
keywords: Gambogic acid; Pulmonary fibrosis; TGF-β1/Smad3; Vasohibin-1; Vasohibin-2