Effect of Nilotinib on Bleomycin-Induced Acute Lung Injury and Pulmonary Fibrosis in Mice

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. Objectives: 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.

[1]  Donna Neuberg,et al.  Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. , 2005, Cancer cell.

[2]  F Verrecchia,et al.  [Cellular and molecular mechanisms of fibrosis]. , 2006, Annales de pathologie.

[3]  J M Simpson,et al.  Simple method of estimating severity of pulmonary fibrosis on a numerical scale. , 1988, Journal of clinical pathology.

[4]  J. Mestan,et al.  Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. , 2005, Biochimica et biophysica acta.

[5]  R. Flavell,et al.  Transforming growth factor-β in T-cell biology , 2002, Nature Reviews Immunology.

[6]  C. Hogaboam,et al.  Murine models of pulmonary fibrosis. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[7]  K. Flanders,et al.  Smad3 is key to TGF-beta-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. , 2006, Cytokine & growth factor reviews.

[8]  L. Papazian,et al.  Pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. A study in mechanically ventilated patients. , 1995, Chest.

[9]  C. Heldin,et al.  Mechanism of action and in vivo role of platelet-derived growth factor. , 1999, Physiological reviews.

[10]  T. Suga,et al.  Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Ligand, Suppresses Bleomycin-Induced Acute Lung Injury and Fibrosis , 2008, Respiration.

[11]  D. Hoyt,et al.  EFFECT OF DOSE OF HYPERTONIC SALINE ON ITS POTENTIAL TO PREVENT LUNG TISSUE DAMAGE IN A MOUSE MODEL OF HEMORRHAGIC SHOCK , 2003, Shock.

[12]  G. Izbicki,et al.  Time course of bleomycin‐induced lung fibrosis , 2002, International journal of experimental pathology.

[13]  D. Schroeder,et al.  Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. , 2010, American journal of respiratory and critical care medicine.

[14]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[15]  M. Gyetko,et al.  Recent advances in molecular targets and treatment of idiopathic pulmonary fibrosis: focus on TGFbeta signaling and the myofibroblast. , 2009, Current medicinal chemistry.

[16]  D. Morgan,et al.  Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. , 1999, The American journal of pathology.

[17]  M. Hacker,et al.  Alteration of bronchoalveolar lavage cell populations following bleomycin treatment in mice. , 1989, Toxicology and applied pharmacology.

[18]  G. Nuovo,et al.  The acute respiratory distress syndrome: a role for transforming growth factor-beta 1. , 2003, American journal of respiratory cell and molecular biology.

[19]  H. Haro,et al.  Imatinib mesylate both prevents and treats the arthritis induced by type II collagen antibody in mice , 2007, Modern rheumatology.

[20]  S. Sone,et al.  Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. , 2005, American journal of respiratory and critical care medicine.

[21]  Kwan Hyung Kim,et al.  Inhaled corticosteroid prevents the thickening of airway smooth muscle in murine model of chronic asthma. , 2008, Pulmonary pharmacology & therapeutics.

[22]  P. Paré,et al.  Platelet-derived growth factor in bronchiolitis obliterans-organizing pneumonia. , 1997, American journal of respiratory and critical care medicine.

[23]  Y. Kaneda,et al.  In Vivo Gene Transfer of an Extracellular Domain of Platelet-Derived Growth Factor β Receptor by the HVJ-Liposome Method Ameliorates Bleomycin-Induced Pulmonary Fibrosis , 1999 .

[24]  D. Hyde,et al.  Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. , 1993, Thorax.

[25]  K. Cutroneo,et al.  A molecular basis for bleomycin-induced pulmonary fibrosis. , 1986, Chest.

[26]  G. Shiha,et al.  Nilotinib counteracts thioacetamide‐induced hepatic oxidative stress and attenuates liver fibrosis progression , 2011, Fundamental & clinical pharmacology.

[27]  M. Jantz,et al.  Pathophysiology of the Pleura , 2008, Respiration.

[28]  H. Joensuu,et al.  Maintained efficacy of the tyrosine kinase inhibitor imatinib mesylate in a patient with rheumatoid arthritis. , 2008, Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases.

[29]  J. Gotlib,et al.  Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. , 2004, Seminars in cancer biology.

[30]  H. Magnussen,et al.  Modulation of fibroblast activity in histiocytosis X by platelet-derived growth factor. , 1995, Chest.

[31]  M. Caligiuri,et al.  Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Oliver Distler,et al.  Dual inhibition of c‐abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  H. Joensuu,et al.  Treatment of rheumatoid arthritis with imatinib mesylate: clinical improvement in three refractory cases , 2003, Annals of medicine.

[34]  A. Schnapp,et al.  Pharmacologic differentiation of inflammation and fibrosis in the rat bleomycin model. , 2006, American journal of respiratory and critical care medicine.

[35]  K. Miyachi,et al.  Efficacy of imatinib mesylate (STI571) treatment for a patient with rheumatoid arthritis developing chronic myelogenous leukemia , 2003, Clinical Rheumatology.

[36]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[37]  R. Nakhleh,et al.  Obliterative bronchiolitis after lung transplantation: a fibroproliferative disorder associated with platelet-derived growth factor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Selman,et al.  Platelet-derived growth factor in idiopathic pulmonary fibrosis. , 1990, The Journal of clinical investigation.

[39]  K Seyama,et al.  Localization of platelet-derived growth factor and insulin-like growth factor I in the fibrotic lung. , 1995, American journal of respiratory and critical care medicine.

[40]  C. Daniels,et al.  Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. , 2004, The Journal of clinical investigation.

[41]  Y. Kaneda,et al.  In vivo gene transfer of an extracellular domain of platelet-derived growth factor beta receptor by the HVJ-liposome method ameliorates bleomycin-induced pulmonary fibrosis. , 1999, Biochemical and biophysical research communications.

[42]  K. Bhalla,et al.  Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. , 2006, The New England journal of medicine.

[43]  B. Wallaert,et al.  Mechanisms of fibrosis in coal workers' pneumoconiosis. Increased production of platelet-derived growth factor, insulin-like growth factor type I, and transforming growth factor beta and relationship to disease severity. , 1994, American journal of respiratory and critical care medicine.

[44]  M. Lamy,et al.  Pathologic features and mechanisms of hypoxemia in adult respiratory distress syndrome. , 1976, The American review of respiratory disease.

[45]  M. Baccarani,et al.  Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. , 2002, Blood.

[46]  J. Chiche,et al.  Transforming growth factor-&bgr;: A mediator of cell regulation in acute respiratory distress syndrome , 2003, Critical care medicine.

[47]  J. Tomashefski,et al.  Pulmonary pathology of the adult respiratory distress syndrome. , 1990, Clinics in chest medicine.

[48]  T. Colby,et al.  Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[49]  D. Fabbro,et al.  Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. , 2006, Gastroenterology.

[50]  E. Buchdunger,et al.  Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. , 2008, European journal of pharmacology.

[51]  D. Fabbro,et al.  Imatinib: a selective tyrosine kinase inhibitor. , 2002, European journal of cancer.

[52]  E. Baxter,et al.  Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. , 2003, Blood.

[53]  D. Schoenfeld,et al.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. , 2000, The New England journal of medicine.

[54]  P. Sime,et al.  TGF-β, Smad3 and the process of progressive fibrosis , 2007 .

[55]  H. Tilg,et al.  The kinase inhibitor imatinib mesylate inhibits TNF-{alpha} production in vitro and prevents TNF-dependent acute hepatic inflammation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.