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-1 and tumor necrosis factor were decreased in the imatinib and Received: April 6, 2010 Accepted after revision: March 18, 2011 Published online: June 9, 2011 Jin Woo Kim Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital , 65-1 Keumho Dong Uijeongbu City , Kyungki Province 480-717 (Korea) Tel. +82 31 820 3995, E-Mail medkjw @ catholic.ac.kr © 2011 S. Karger AG, Basel 0025–7931/11/0823–0273$38.00/0 Accessible online at: www.karger.com/res Rhee /Lee /Yoon /Kim /Lee /Kwon /Kim / Kim /Kim /Kim Respiration 2011;82:273–287 274 apies are available currently. ALI/ARDS is considered to have an early and a late phase. The early phase is characterized by inflammatory injury and the late, so-called fibroproliferative, phase is characterized by collagen deposition with tissue remodeling [3, 4] . Experimentally, intratracheal delivery of bleomycin has been shown to induce lung injury and fibrosis in a wide variety of experimental animals, including mice [5] . The tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec /Glivec ; Novartis International AG, Basel, Switzerland) was developed as an inhibitor of the tyrosine kinase activity of the oncogene fusion protein BCR-ABL. Imatinib has shown significant activity in treating patients with chronic myeloid leukemia (CML) [6, 7] . However, imatinib also has potent inhibitory activity against kinase activity associated with the stem cell factor (c-Kit), discoidin domain receptor and the plateletderived growth factor receptor (PDGFR) [8, 9] . Imatinib has also demonstrated efficacy against gastrointestinal stromal tumor and hypereosinophilic syndrome, as a result of Kit and PDGFR inhibition [10–12] . Recently, nilotinib (AMN107, Tasigna ; Novartis) has been approved for treating patients with BCR-ABL-positive CML with resistance or intolerance to imatinib. Nilotinib is also a small molecule tyrosine kinase inhibitor that can be administrated orally [13] . Like imatinib, nilotinib inhibits the tyrosine kinase activity of Abl-kinase, c-Kit, discoidin domain receptor and PDGFR. Comparison of the half-maximal inhibitory concentration showed nilotinib to be more potent than imatinib. Nilotinib also showed good bioavailability [14] . Consistent with its in vitro and pharmacokinetic profiles, nilotinib prolonged survival in imatinib-resistant CML mouse models [15] . A previous report showed that imatinib could attenuate bleomycin-induced fibrosis in mice [16] . However, that report focused only on fibrosis. Moreover, there has been no study on the effects of nilotinib on bleomycininduced ALI and pulmonary fibrosis. Therefore, the present study aimed to determine whether imatinib and nilotinib could attenuate ALI and pulmonary fibrosis in a mouse model of disease induced by bleomycin and to evaluate their effects on the signal transduction pathway responsible for inflammatory and fibrotic responses.