Increased fibroblast growth factor 10 (Fgf10) expression in vivo and administration of exogenous FGF7 recombinant protein enhance lung repair due to bleomycin injury by sending survival signals to lung epithelial cells via tyrosine kinase fibroblast growth factor receptor 2b (Fgfr2b). Given the prophylactic effects of FGF7 and therapeutic effects of FGF10 during bleomycin injury in mice, it was hypothesized that activation of the Fgfr2b endogenous pathway is critical for lung repair after bleomycin injury in mice. Furthermore, as new studies for the treatment of Idiopathic Pulmonary Fibrosis (IPF) have begun to target tyrosine kinases, the aim was to 1) assess the levels of FGF10 and FGF7 signaling in end-stage IPF lungs, 2) assess the level of recruitment of the endogenous Fgfr2b pathway after bleomycin lung injury in mice, and 3) assess the effect of FGF10 treatment on IPF fibroblasts in vitro.Compared to donor, non-IPF controls, FGF7 and FGF10 transcripts were increased in end-stage IPF patient lung homogenates. However, receptors as well as downstream targets of FGF7 and 10 were significantly decreased. In contrast, wild type mice undergoing spontaneous repair after bleomycin injury, expressed Fgf10 and downstream targets from 14 days post injury, indicating potential recruitment of this pathway during repair. Using three different genetic mouse lines congenitally deficient in endogenous Fgfr2b signaling, we found that Fgf10 deficient animals incurred the highest trend towards increased fibrosis. Surprisingly, in a fourth mouse line allowing for induction of a soluble, dominant negative Fgfr2b receptor, induced mice did not show increased bleomycin-induced fibrosis compared to non-induced controls. Thus FGFR2b ligands signaling seemed to be recruited in a model of spontaneous repair, and dysregulated in non- repairing IPF patients. Thus the endogenous FGFR2b pathway may be redundant with other repair pathways in mice, as attenuating it did not result in a significant increase in bleomycin- induced fibrosis.IPF fibroblasts responded to FGF10 treatment by decreasing their size, increasing proliferation and increasing expression of lipofibroblast markers. In addition, FGF10 inhibited transforming growth factor beta (TGF-ß) stimulated induction of TGF-ß signaling downstream target, pSMAD3. Likewise the ability of FGF10 to reduce cell size and inhibit TGF-ß signaling in IPF fibroblasts, suggests that it could effectively mediate a contractile to synthetic-like phenotype, which may be an important step towards UIP lesion repair.Taken together, this work highlights and discusses 1) the attenuation of FGFR2b ligand signaling in end-stage IPF, 2) FGFR2b signaling recruitment in wild type mice during bleomycin injury, yet redundant role in injury, and 3) the potential therapeutic effect of FGF10 given the effects of treatment on IPF fibroblasts.
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