Chaudhary N I, Roth G J, Hilberg F, Müller-Quernheim J, Prasse A, Zissel G, Schnapp A, Park J E
Dept of Pulmonary Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstrasse 65, D-88937, Biberach an der Riss, Germany.
Eur Respir J. 2007 May;29(5):976-85. doi: 10.1183/09031936.00152106. Epub 2007 Feb 14.
BIBF 1000 is a small molecule inhibitor targeting the receptor kinases of platelet-derived growth factor (PDGF), basic fibroblast growth factor and vascular endothelial growth factor, which have known roles in the pathogenesis of pulmonary fibrosis. The anti-fibrotic potential of BIBF 1000 was determined in a rat model of bleomycin-induced lung fibrosis and in an ex vivo fibroblast differentiation assay. Rats exposed to a single intra-tracheal injection of bleomycin were treated with BIBF 1000 starting 10 days after bleomycin administration. To gauge for anti-fibrotic activity, collagen deposition and pro-fibrotic growth factor gene expression was analysed in isolated lungs. Furthermore, the activity of BIBF 1000 was compared with imatinib mesylate (combined PDGF receptor, c-kit and c-abl kinase inhibitor) and SB-431542 (transforming growth factor (TGF)-beta receptor I kinase inhibitor) in an ex vivo TGF-beta-driven fibroblast to myofibroblast differentiation assay, performed in primary human bronchial fibroblasts. Treatment of rats with BIBF 1000 resulted in the attenuation of fibrosis as assessed by the reduction of collagen deposition and the inhibition of pro-fibrotic gene expression. In the cellular assay both SB-431542 and BIBF 1000 showed dose-dependent inhibition of TGF-beta-induced differentiation, whereas imatinib mesylate was inactive. BIBF 1000, or related small molecules with a similar kinase inhibition profile, may represent a novel therapeutic approach for the treatment of idiopathic pulmonary fibrosis.
BIBF 1000是一种小分子抑制剂,靶向血小板衍生生长因子(PDGF)、碱性成纤维细胞生长因子和血管内皮生长因子的受体激酶,这些激酶在肺纤维化的发病机制中具有已知作用。在博来霉素诱导的肺纤维化大鼠模型和体外成纤维细胞分化试验中测定了BIBF 1000的抗纤维化潜力。经气管内单次注射博来霉素的大鼠在给予博来霉素10天后开始用BIBF 1000治疗。为了评估抗纤维化活性,对分离的肺组织中的胶原沉积和促纤维化生长因子基因表达进行了分析。此外,在原代人支气管成纤维细胞中进行的体外转化生长因子(TGF)-β驱动的成纤维细胞向肌成纤维细胞分化试验中,将BIBF 1000的活性与甲磺酸伊马替尼(联合PDGF受体、c-kit和c-abl激酶抑制剂)和SB-431542(TGF-β受体I激酶抑制剂)进行了比较。用BIBF 1000治疗大鼠导致纤维化减轻,这通过胶原沉积减少和促纤维化基因表达抑制来评估。在细胞试验中,SB-431542和BIBF 1000均显示出对TGF-β诱导分化的剂量依赖性抑制,而甲磺酸伊马替尼无活性。BIBF 1000或具有类似激酶抑制谱的相关小分子可能代表了一种治疗特发性肺纤维化的新治疗方法。