Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis

Abstract

BIBF 1000 is a small molecule inhibitor targeting the receptor kinases of plateletderived 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 intratracheal 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)-b receptor I kinase inhibitor) in an ex vivo TGF-bdriven 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-b-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.

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…These growth factors are known as fibrogenic mediators promoting fibroblast proliferation and matrix contraction. BIBF has been applied orally from day 10 to day 21 in the bleomycin treated rat model leading to reduced gene expression of transforming growth factor (TGF)-β1, procollagen-1, fibronectin and connective tissue growth factor (CTGF), as well as less collagen staining in treated animals compared to bleomycin controls (Chaudary NI, 2007). This compound is currently entering clinical trials in IPF.…”

Role of α1 and α2 chains of type IV collagen in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts

“…Because TGF-β1 stimulation has been reported to induce α-SMA expression in fibroblasts as differentiation into myofibroblasts for 1 to 4 days, [19][20][21] we cultured the cells for 0 to 168 h (7 days) with TGF-β1 treatment to examine the effect of TGF-β1 on mRNA expression of α(IV) chains in TIG-1-20 cells at various time points. We confirmed that the mRNA expression of α1(IV) and α2(IV) chains was upregulated in TIG-1-20 cells up to 96 h (4days; Supplementary Figure 2).…”

Evaluation the adjunctive use of combined bevacizumab and mitomycinc to trabeculectomy in management of recurrent pediatric glaucoma

“…VEGF inhibition not only reduced the amount of scar formed but also improved the quality of the scar tissue by shifting the collagen fibril distribution in a manner that is similar to that of normal tissue. 21 The subconjunctival injection of bevacizumab was found to be associated with improvements in trabeculectomy bleb survival in glaucoma, which suggests that bevacizumab may be a useful agent for improving the success rate and limiting scar tissue formation after trabeculectomy. 22 This study aimed to evaluate the additive effect of bevacizumab to MMC-augmented trabeculectomy in recurrent cases of childhood glaucoma concerning its efficacy and complications.…”