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  • In addition to through direct regulation of cell

    2021-07-27

    In addition to through direct regulation of cell differentiation, DDR2 may raise the abundance of myofibroblast subsets through advancing the recruitment of its precursor cells. One such evidence is that DDR2 can regulate lung fibroblast proliferation and migration. Another possibility rests on the established concepts that alveolar epithelial Apocynin receptor can serve as an important source of lung fibroblasts via EMT,, and that DDR2 is a critical regulator of EMT.,, A most recent study reported that DDR2 can regulate neutrophil chemotaxis. Given neutrophil's well-characterized contribution to IPF, we do not exclude the possibility that such a regulatory link may also exist in the bleomycin-treated model, although we did not investigate this point. However, even with this possibility, our results showing that starting DDR2 siRNA treatment from day 14, a time point of maximal injury as well as the onset of tissue remodeling, had similar protective effect as prevention schedule, give a clue that DDR2 control of postinflammation events might determine its influence on the final outcome of fibrosis. We recently demonstrated that DDR2 promotes the angiogenic activity of endothelial cells in vitro. However, according to the in vivo data from our lab and others,, DDR2-deficient stroma can also accelerate angiogenesis under some pathological conditions. We reasoned that the positive regulation of DDR2 on endothelial function may be overbalanced out by its negative modulation on surrounding cell secretion of proangiogenic cytokines, finally making DDR2 gives rise to an overall inhibitory outcome in angiogenesis. In this study, we found that DDR2 enhances both TGF-β1- and collagen I-driven expression of VEGF-A in lung fibroblasts. This in vitro evidence coincides with the in vivo observation that a genetic deficiency of Ddr2 impedes lung neovascularization in bleomycin-induced fibrosis model. Accumulating evidences indicate that antiangiogenesis therapy may be a promising treatment option for pulmonary fibrosis.,, Notably, nintedanib, a triple angiokinase inhibitor (VEGFR, platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor (FGFR)), recently became the first approved drug for IPF treatment. Therefore, our current data collectively indicate that DDR2 control of lung myofibroblast behaviors could produce impacts on both angiogenic and fibrotic processes. Although dasatinib does not distinguish DDR2 from DDR1 whose knockout mice were similarly refractory to bleomycin-induced lung fibrosis,, it is unlikely that the therapeutic effects of dasatinib treatment starting from 14 days after bleomycin in our model could equally benefit from its inhibition of the two members because DDR1 was considered to primarily regulate the function of epithelial cells and macrophages., The expression of DDR1 in lung fibroblasts, although positive, was reported to rely on DDR2 signaling. Whatever, multitarget effect is a common characteristic for most kinase inhibitors, which sometimes is conducive to enhancing their efficacy in inhibiting disease progression. For instance, dasatinib suppression of Src activity may additionally contribute to the action of this drug on TGF-β-induced myofibroblast events because Src kinase was reported to serve as a key mediator of TGF-β–p38 pathway., The results derived by the authors, together with the most recently published data, provide important preclinical evidence for the use of dasatinib in the treatment of IPF.
    Materials and Methods The heterozygous slie mutant mice, carrying deletion mutation spanning Ddr2 exon 1–17, were provided by Jackson Lab (Bar Harbor, Maine) and intercrossed to produce homozygotes for use. All animal studies were performed according to the protocols and guidelines of the institutional care and use committee. To induce pulmonary damage, 6- to 8-week-old sex- and age-matched wild-type or slie mice were intranasally dropped with bleomycin (Nippon Kayaku, Tokyo, Japan) at 5 mg/kg body weight (BW) or FITC (Sigma, St Louis, MO) at 6 mg/kg BW. For in vivo silencing of DDR2 in mouse lung, a nonspecific control siRNA or DDR2-specific siRNA was modified with 2′-methoxy (2′-OMe) by Genepharma Company (Shanghai, China) to improve stability. The sense sequences of siRNAs are as following: DDR2, 5′-TTGAGATGAATACTAGCTTAG-3′; control, 5′-TTCTCCGAACGTGTCACGTT-3′. The silencing effect of DDR2 siRNA has been validated by our previous in vitro study. One OD siRNA was dissolved in 40 μl D5W solution (5% D-Glucose) and used to treat one mouse per time through nasal instillation as described earlier. For each group, the siRNA treatment was conducted once a week before the harvest. Dasatinib (Sprycel, Bristol-Myers Squibb, New York, NY) was dissolved in 80 mmol/l citric acid (pH 2.1) to make a stock solution of 10 mg/ml. For animal use, dasatinib were given to the mice orally (10 mg/kg BW) by gavage once a day. At least five animals were used in each treatment group and three individual experiments were performed.