title: Protective role of rhapontin in experimental pulmonary fibrosis in vitro and in vivo.
abstract: BACKGROUND
  Pulmonary fibrosis is a scaring process related to chronic lung injury of all causes. The treatment options for pulmonary fibrosis are very limited. Rhapontin has anti-inflammatory effect and anti-proliferative activity which is widely distributed in the medicinal plants of Rheum genus in China. However, the anti-fibrotic activities of rhapontin have not been previously investigated.
  
  
  METHODS
  The effect of rhapontin on TGF-β1-mediated extracellular matrix (ECM) deposition in primary lung fibroblast (PLF) cells, on TGF-β1 secretion in LPS-stimulated human THP-1 derived macrophages in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis was investigated in vivo. Fibrotic mice were induced by intratracheal instillation of bleomycin, and then treated with rhapontin (25, 50, or 100mg/kg/day) or prednisone (6.5mg/kg/day, positive drug) for 2weeks.
  
  
  RESULTS
  In TGF-β1 stimulated PLFs, treatment with rhapontin resulted in a reduction of ECM with a decrease in Lox2 and p-Smad2/3. In LPS activated macrophages, treatment with rhapontin reduced TGF-β1 production. However, in vitro the attenuated ECM deposition and inflammatory response by rhapontin were closely associated with AMPK activation, and these suppression of rhapontin were significantly abolished by the AMPK inhibitor. Treatment with rhapontin for 2weeks resulted in an amelioration of the BLM-induced pulmonary fibrosis in rats with a lower Lox2, whereas a higher AMPK expression, with reductions of the pathological score, collagen deposition, TGF-β1, α-SMA, Lox2, and HIF-1α expressions in lung tissues at fibrotic stage at 100mg/kg.
  
  
  CONCLUSIONS
  In summary, rhapontin reversed ECM, as well as Lox2 proliferation in vitro and prevented pulmonary fibrosis in vivo by modulating AMPK activation and suppressing the TGF-β/Smad pathway.
authors.affiliation: Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Tao
authors.affiliation: Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Cao
authors.affiliation: Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Wei
authors.affiliation: Chengdu biopurity phytochemicals Ltd., Chengdu 611131, People's Republic of China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Xie
authors.affiliation: Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
authors.forename: Mian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing 211198, People's Republic of China. Electronic address: zhangchaofeng@cpu.edu.cn.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008516:Medicine, Chinese Traditional; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D012250:Rheum / Q000276:immunology; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013267:Stilbenes / Q000627:therapeutic use*; D000074084:THP-1 Cells; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D051785:Smad Proteins; D013267:Stilbenes; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; C023538:rhapontin
keywords: AMPK; Lung fibroblast; Pulmonary fibrosis; Rhapontin; TGF-β/Smad pathway