title: VEGFR-2 antagonist SU5416 attenuates bleomycin-induced pulmonary fibrosis in mice.
abstract: OBJECTIVE
  Abnormal angiogenesis is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. It has been shown that vascular endothelial growth factor (VEGF) is one of the critical angiogenic factors in angiogenesis. The aim of the present study was to assess whether disruption of VEGF pathway would attenuate bleomycin-induced pulmonary fibrosis.
  
  
  METHODS
  Bleomycin-induced pulmonary fibrosis mice were treated intraperitoneally with VEGF receptor tyrosine kinase inhibitor SU5416 at different phases after bleomycin infusion. We measured angiogenesis and inflammatory response in both bleomycin-treated and control mice, and correlated these levels with pulmonary fibrosis.
  
  
  RESULTS
  The increased expressions of VEGF/VEGFR (Flk-1) were correlated to a larger number of microvessels and a higher score of pulmonary fibrosis. Early administration of SU5416 inhibited pulmonary collagen deposition, histopathologic fibroplasias and the activation of TGF-beta1/Smad3 signaling pathway in bleomycin-stimulated lung. These were also paralleled by a reduction of VEGF/VEGFR-2 (Flk-1) expression and microvessel numbers in lung. Furthermore, SU5416 inhibited inflammatory cell numbers and LDH activity in BALF and IL-13 expression in lung tissue at early inflammatory phase of bleomycin-induced pulmonary fibrosis.
  
  
  CONCLUSIONS
  These results suggest that the VEGFR-2 inhibitor, SU5416, attenuates histopathologic fibroplasias and collagen deposition by regulating angiogenesis and inflammation in the lung.
authors.affiliation: Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Ou
authors.forename: Wan-Cheng
authors.initials: WC
authors.lastname: Li
authors.forename: Dai-Shun
authors.initials: DS
authors.lastname: Liu
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Li
authors.forename: Fu-Qiang
authors.initials: FQ
authors.lastname: Wen
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Feng
authors.forename: Shang-Fu
authors.initials: SF
authors.lastname: Zhang
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Huang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001761:Bleomycin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D005434:Flow Cytometry; D006909:Hydroxyproline / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D011758:Pyrroles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D007211:Indoles; D011758:Pyrroles; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D001761:Bleomycin; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2; D006909:Hydroxyproline