title: Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice.
abstract: BACKGROUND
  The tyrosine kinase inhibitor imatinib mesylate was developed as an inhibitor of the kinase activity of BCR-ABL. However, imatinib also has potent inhibitory activity against the platelet-derived growth factor receptor (PDGFR). Nilotinib is approved for treating patients with chronic myeloid leukemia showing resistance or intolerance to imatinib. Like imatinib, nilotinib selectively inhibits the tyrosine kinase activity of PDGFR.
  
  
  OBJECTIVE
  We examined the effect of imatinib and nilotinib on acute lung injury and pulmonary fibrosis in a mouse model.
  
  
  METHODS
  Mice were treated by intratracheal instillation of bleomycin. Imatinib or nilotinib were administered by oral gavage. To study the early inflammatory and late fibrotic phases of lung injury, mice were sacrificed on days 3, 7, 14 and 21 after bleomycin instillation.
  
  
  RESULTS
  Histopathology showed that imatinib and nilotinib attenuated the extent of lung injury and fibrosis. The numbers of inflammatory cells and levels of IL-6, IL-1β and tumor necrosis factor-α were decreased in the imatinib and nilotinib groups on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline on days 14 and 21, which was accompanied by decreased expression levels of transforming growth factor (TGF)-β1 and PDGFR-β. Imatinib and nilotinib also significantly reduced the expression levels of the genes for TGF-β1 and platelet-derived growth factor (PDGF). Imatinib and nilotinib treatment also significantly inhibited the PDGF-induced proliferation of lung fibroblasts in vitro. When imatinib or nilotinib was given 7 days after the instillation of bleomycin, only nilotinib attenuated pulmonary fibrosis.
  
  
  CONCLUSIONS
  Imatinib and nilotinib attenuated bleomycin-induced acute lung injury and pulmonary fibrosis in mice. In a therapeutic model, nilotinib showed more potent antifibrotic effects than imatinib.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, College of Medicine, Catholic University of Korea, Seoul, Korea.
authors.forename: Chin Kook
authors.initials: CK
authors.lastname: Rhee
authors.forename: Sang Haak
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyung Kyu
authors.initials: HK
authors.lastname: Yoon
authors.forename: Seok Chan
authors.initials: SC
authors.lastname: Kim
authors.forename: Sook Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Soon Suk
authors.initials: SS
authors.lastname: Kwon
authors.forename: Young Kyoon
authors.initials: YK
authors.lastname: Kim
authors.forename: Kwan Hyoung
authors.initials: KH
authors.lastname: Kim
authors.forename: Tae Jung
authors.initials: TJ
authors.lastname: Kim
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000378:metabolism; D001761:Bleomycin / Q000009:adverse effects*; D015153:Blotting, Western; D005786:Gene Expression Regulation; D000068877:Imatinib Mesylate; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D001549:Benzamides; D014408:Biomarkers, Tumor; D053583:Interleukin-1beta; D015850:Interleukin-6; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib