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Effect of Imatinib and Nilotinib on Bleomycin-Induced Acute Lung Injury and Pulmonary Fibrosis
October 2010, Vol 138, No. 4_MeetingAbstracts Poster Presentations: Tuesday, November 2, 2010 | October 2010
Effect of Imatinib and Nilotinib on Bleomycin-Induced Acute Lung Injury and Pulmonary Fibrosis Hyoung Kyu Yoon, MD; Sang Haak Lee, MD; Yong Hyun Kim; Seok Chan Kim, MD; Chi Hong Kim, MD; Young Kyoon Kim, MD; Hwa Sik Moon, MD; Joong Hyeun Ahn, MD; Sung Hak Park, MD; Jin Woo Kim Catholic University of Medical Center, Uijongbu, South Korea Chest. 2010;138(4_MeetingAbstracts):221A. doi:10.1378/chest.10166 Abstract PURPOSE: To demonstrate this effect, we evaluated (1) The effects of imatinib/nilotinib on acute lung injury and fibrotic changes induced by bleomycin (2) The effects on the signal transduction pathway responsible for inflammatory and fibrotic responses To see the sequential change of lung injury and fibrosis, we examined animal model on day 3, 7, 14 and 21. METHODS: Animalmale C57BL6 mice, 6 weeks of age(1) Control(2) Bleomycin (3) Bleomycin + Imatinib(100mg/kg, twice-daily)(4) Bleomycin + Nilotinib(100mg/kg, once-daily)In vitro studyNIH3T3Fibroblast0703 \Bleomycin Administrated via intratracheal instillation (1.5 U/kg) on day 0Imatinib / nilotinib administrated by oral gavage Starting on 3 days before bleomycin administration continuing till sacrifice. Sacrifice On days 3, 7, 14, and 21 BALF cell count analysisELISA in BALF : TGF-β1, IL-6, IL-1β, TNF-α Collagen assay in lung tissue : hydroxyproline Western in lung tissue : p-Smad 2,3,7, TGF-β1, PDGFR-βRT-PCR in lung tissue : TGF-β1, PDGFRT-PCR in cell line : PDGF-AA, PDGF-BB. RESULTS: Histological examination showed imatinib and nilotinib attenuated lung injury and fibrosis. The number of inflammatory cells and levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α were decreased in imatinib and nilotinib group on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline and transforming growth factor (TGF)-β1 on days 14 and 21, which was accompanied by the decreased expression of TGF-β1 and PDGFR-β. Imatinib and nilotinib also significantly reduced the gene expression of TGF-β1 and PDGF. In vitro experiment, imatinib and nilotinib significantly inhibited the PDGFinduced proliferation of lung fibroblasts. CONCLUSION: Imatinib&nilotinib attenuated bleomycin-induced ALI on day 3&7Imatinib&nilotinib attenuated bleomycin-induced pulmonary fibrosis on day 14&21Further investigation is needed into the mechanisms through which pravastatin inhibits ALI and pulmonary fibrosis. CLINICAL IMPLICATIONS: Imatinib&nilotinib are potential treatment strategy for acute lung injury and fibrosis. DISCLOSURE: Jin Woo Kim, No Financial Disclosure Information; No Product/Research Disclosure Information 12:45 PM - 2:00 PM
Effect of Imatinib and Nilotinib on Bleomycin-Induced Acute Lung Injury and Pulmonary Fibrosis Hyoung Kyu Yoon, MD; Sang Haak Lee, MD; Yong Hyun Kim; Seok Chan Kim, MD; Chi Hong Kim, MD; Young Kyoon Kim, MD; Hwa Sik Moon, MD; Joong Hyeun Ahn, MD; Sung Hak Park, MD; Jin Woo Kim Catholic University of Medical Center, Uijongbu, South Korea Chest. 2010;138(4_MeetingAbstracts):221A. doi:10.1378/chest.10166 Abstract PURPOSE: To demonstrate this effect, we evaluated (1) The effects of imatinib/nilotinib on acute lung injury and fibrotic changes induced by bleomycin (2) The effects on the signal transduction pathway responsible for inflammatory and fibrotic responses To see the sequential change of lung injury and fibrosis, we examined animal model on day 3, 7, 14 and 21. METHODS: Animalmale C57BL6 mice, 6 weeks of age(1) Control(2) Bleomycin (3) Bleomycin + Imatinib(100mg/kg, twice-daily)(4) Bleomycin + Nilotinib(100mg/kg, once-daily)In vitro studyNIH3T3Fibroblast0703 \Bleomycin Administrated via intratracheal instillation (1.5 U/kg) on day 0Imatinib / nilotinib administrated by oral gavage Starting on 3 days before bleomycin administration continuing till sacrifice. Sacrifice On days 3, 7, 14, and 21 BALF cell count analysisELISA in BALF : TGF-β1, IL-6, IL-1β, TNF-α Collagen assay in lung tissue : hydroxyproline Western in lung tissue : p-Smad 2,3,7, TGF-β1, PDGFR-βRT-PCR in lung tissue : TGF-β1, PDGFRT-PCR in cell line : PDGF-AA, PDGF-BB. RESULTS: Histological examination showed imatinib and nilotinib attenuated lung injury and fibrosis. The number of inflammatory cells and levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α were decreased in imatinib and nilotinib group on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline and transforming growth factor (TGF)-β1 on days 14 and 21, which was accompanied by the decreased expression of TGF-β1 and PDGFR-β. Imatinib and nilotinib also significantly reduced the gene expression of TGF-β1 and PDGF. In vitro experiment, imatinib and nilotinib significantly inhibited the PDGFinduced proliferation of lung fibroblasts. CONCLUSION: Imatinib&nilotinib attenuated bleomycin-induced ALI on day 3&7Imatinib&nilotinib attenuated bleomycin-induced pulmonary fibrosis on day 14&21Further investigation is needed into the mechanisms through which pravastatin inhibits ALI and pulmonary fibrosis. CLINICAL IMPLICATIONS: Imatinib&nilotinib are potential treatment strategy for acute lung injury and fibrosis. DISCLOSURE: Jin Woo Kim, No Financial Disclosure Information; No Product/Research Disclosure Information 12:45 PM - 2:00 PM