Inhibition of PDGF VEGF and FGF signalling attenuates fibrosis

¹ Dept of Pulmonary Research
² Dept of Chemical Research, Boehringer Ingelheim Pharma GmbH & Co. KG, D-88937 Biberach an der Riss, Germany
³ Dept of Oncology Research, Boehringer Ingelheim Austria GmbH, Vienna, Austria
⁴ Dept of Pneumology, Medical Centre, University Hospital Freiburg, Germany

^* To whom correspondence should be addressed. E-mail: andreas.schnapp{at}bc.boehringer-ingelheim.com.

	Abstract

BIBF1000 is a small molecule inhibitor targeting the receptor kinases of PDGF, bFGF and VEGF, which have known roles in the pathogenesis of pulmonary fibrosis.

The anti-fibrotic potential of BIBF1000 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 BIBF1000 starting 10 days after bleomycin administration. To gauge for anti-fibrotic activity, collagen deposition and pro-fibrotic growth factor gene expression was analyzed in isolated lungs. Furthermore, the activity of BIBF1000 was compared to imatinib mesylate (combined PDGFR, c-kit, c-abl kinase inhibitor) and SB-431542 (TGF receptor I kinase inhibitor) in an ex vivo TGF-driven fibroblast to myofibroblast differentiation assay, performed in primary human bronchial fibroblasts.

Treatment of rats with BIBF1000 resulted in 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 BIBF1000 showed dose-dependent inhibition of TGF-induced differentiation whereas imatinib mesylate was inactive.

BIBF1000, or related small molecules with a similar kinase inhibition profile, may represent a novel therapeutic approach for the treatment of IPF.

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