title: Amelioration of bleomycin-induced pulmonary fibrosis in a mouse model by a combination therapy of bosentan and imatinib.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is characterized by alveolitis, progressing into fibrosis. Due to the involvement of both endothelin and platelet-derived growth factor signaling in IPF, combination effects of a bosentan and imatinib were studied in mouse model of bleomycin-induced pulmonary fibrosis.
  
  
  METHODS
  Mice subjected to bleomycin instillation (0.05 U) and were administered with either bosentan (100 mg/kg) and/or imatinib (50 mg/kg). Inflammatory cell count, total protein estimation in bronchoalveolar lavage fluid, lung edema, superoxide dismutase, catalase, myeloperoxidase activities, and Hematoxylin & Eosin staining were performed on day 7. Hydroxyproline content, α-smooth muscle actin (SMA), collagens I and III gene expression analysis, immunohistochemistry, matrix metalloproteinases-9 and -2 activities, trichrome and sirius red staining were performed on day 21.
  
  
  RESULTS
  Combination treatment with bosentan and imatinib prevented bleomycin-induced mortality and loss of body weight more than the individual agents. On day 7, the combination therapy attenuated bleomycin-induced increase of total and differential inflammatory cell counts, total proteins, lung wet/dry weight ratio, myeloperoxidase activity, lung inflammatory cell infiltration more than individual agents alone. Bosentan but not imatinib ameliorated superoxide dismutase and catalase activities, which were lowered following bleomycin instillation. On day 21, combination therapy ameliorated bleomycin-induced increase of fibrosis score, collagen deposition, protein and gene expression of SMA, mRNA levels of collagens-I and -III, matrix metalloproteinase-9 and -2 activities more than monotherapy.
  
  
  CONCLUSIONS
  Combination of bosentan and imatinib exerted more enhanced protection against bleomycin-induced inflammation and fibrosis than either of the agents alone.
authors.affiliation: 1Sugen Life Sciences Pvt. Ltd., Tirupati, Andhra Pradesh, India.
authors.forename: Shanmuga Reddy
authors.initials: SR
authors.lastname: Chilakapati
authors.forename: Mamatha
authors.initials: M
authors.lastname: Serasanambati
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Vissavajjhala
authors.forename: Jagadeeshwara Reddy
authors.initials: JR
authors.lastname: Kanala
authors.forename: Damodar Reddy
authors.initials: DR
authors.lastname: Chilakapati
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001761:Bleomycin; D000077300:Bosentan; D002374:Catalase / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006909:Hydroxyproline / Q000378:metabolism; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000517:prevention & control; D011654:Pulmonary Edema / Q000139:chemically induced / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
chemical_list: D000199:Actins; D000893:Anti-Inflammatory Agents; D024042:Collagen Type I; D024043:Collagen Type II; D012333:RNA, Messenger; D013449:Sulfonamides; C544013:alpha-smooth muscle actin, mouse; D001761:Bleomycin; D000068877:Imatinib Mesylate; D002374:Catalase; D009195:Peroxidase; D013482:Superoxide Dismutase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000077300:Bosentan; D006909:Hydroxyproline
keywords: bleomycin; bosentan; collagen; imatinib; inflammatory cells; pulmonary fibrosis