The main event in the progression of pulmonary fibrosis is the appearance of myofibroblasts. Recent evidence supports pericytes as a major source of myofibroblasts. TGFβ/Smad2/3 and PDGF/Erk signaling pathways are important for regulating pericyte activation. Previous studies have demonstrated that PDGFβR and TGFβR are modified by core fucosylation (CF) catalyzed by α-1,6-fucosyltransferase (FUT8). The aim of this study was to compare the effect of inhibiting CF versus the PDGFβR and TGFβR signaling pathways on pericyte activation and lung fibrosis. FUT8shRNA was used to knock down FUT8-mediated CF both in vivo and in isolated lung pericytes. The small molecule receptor antagonists, ST1571 (imatinib) and LY2109761, were used to block the PDGFβ/pErk and TGFβ/pSmad2/3 signaling pathways, respectively. Pericyte detachment and myofibroblastic transformation were assessed by immunofluorescence and Western blot. Histochemical and immunohistochemical staining were used to evaluate the effect of the intervention on pulmonary fibrosis. Our findings demonstrate that FUT8shRNA significantly blocked pericyte activation and the progression of pulmonary fibrosis, achieving intervention effects superior to the small molecule inhibitors. The PDGFβ and TGFβ pathways were simultaneously affected by the CF blockade. FUT8 expression was upregulated with the transformation of pericytes into myofibroblasts, and silencing FUT8 expression inhibited this transformation. In addition, there is a causal relationship between CF modification catalyzed by FUT8 and pulmonary fibrosis. Our findings suggest that FUT8 may be a novel therapeutic target for pulmonary fibrosis.

肺纤维化进展中的主要事件是肌成纤维细胞的出现。最近的证据支持周细胞是成肌纤维细胞的主要来源。TGFβ/ Smad2 / 3和PDGF / Erk信号通路对于调节周细胞活化很重要。先前的研究表明，PDGFβR和TGFβR被α-1,6-岩藻糖基转移酶（FUT8）催化的岩藻糖基化（CF）修饰。这项研究的目的是比较抑制CF与PDGFβR和TGFβR信号通路对周细胞活化和肺纤维化的作用。FUT8shRNA用于体内和分离的肺周细胞中敲低FUT8介导的CF。小分子受体拮抗剂ST1571（imatinib）和LY2109761被分别用来阻断PDGFβ/ pErk和TGFβ/ pSmad2 / 3信号通路。通过免疫荧光和蛋白质印迹评估周细胞脱离和肌纤维母细胞转化。组织化学和免疫组织化学染色用于评估干预对肺纤维化的作用。我们的发现表明，FUT8shRNA显着阻断了周细胞活化和肺纤维化的进程，取得了优于小分子抑制剂的干预作用。CF阻滞同时影响PDGFβ和TGFβ途径。FUT8表达随着周细胞向成肌纤维细胞的转化而上调，而沉默FUT8表达则抑制了这种转化。此外，FUT8催化的CF修饰与肺纤维化之间存在因果关系。我们的发现表明FUT8可能是肺纤维化的新型治疗靶标。