Dedicator of cytokinesis 2 (DOCK2) deficiency attenuates lung injury associated with chronic high-fat and high-fructose diet-induced obesity.
Dedicator of cytokinesis 2 (DOCK2) deficiency attenuates lung injury associated with chronic high-fat and high-fructose diet-induced obesity.
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DOI：
10.1016/j.ajpath.2021.10.011
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发表时间：
2021-11
期刊：
影响因子：
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通讯作者：
G. Qian;O. Adeyanju;C. Sunil;Steven K. Huang;Shi-You Chen;T. Tucker;S. Idell;Xia Guo
中科院分区：
文献类型：
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作者：
G. Qian;O. Adeyanju;C. Sunil;Steven K. Huang;Shi-You Chen;T. Tucker;S. Idell;Xia Guo
肥胖是肺部疾病发展的主要危险因素。然而，关于慢性高脂肪和高果糖（HFHF）饮食诱导的肥胖对肺部炎症和随后的肺纤维化的影响知之甚少。在此，我们假设胞质分裂贡献因子2（DOCK 2）促进肺成纤维细胞（LF）的促炎表型，从而在慢性HFHF饮食诱导的肥胖中引起肺损伤和纤维化。HFHF饮食20周诱导野生型C57 BL/6小鼠的肺部炎症和促纤维化变化。CD 68和单核细胞趋化蛋白-1（MCP-1）的表达在喂食HFHF饮食的野生型小鼠的肺中显著增加。HFHF饮食进一步增加与成纤维细胞特异性蛋白1共定位的肺DOCK 2表达，表明DOCK 2在调节LF的促炎表型中的作用。重要的是，DOCK 2敲除保护小鼠免受HFHF饮食诱导的肺部炎症和纤维化。在原代人LF中，肿瘤坏死因子-α（TNF-α）和IL-1β诱导DOCK 2表达，同时诱导MCP-1、IL-6和基质金属肽酶2表达。DOCK 2敲低抑制TNF-α诱导的这些分子的表达以及磷脂酰肌醇3-激酶/AKT和NF-κB信号通路的激活，提示DOCK 2介导的人LF促炎和促纤维化变化的机制。总之，这些发现揭示了DOCK 2在调节LF的促炎表型、增强肺部炎症和慢性HFHF饮食引起的肥胖中的肺纤维化中的先前未被认识的作用。
Obesity is a major risk factor for lung disease development. However, little is known about the impact of chronic high-fat and high-fructose (HFHF) diet–induced obesity on lung inflammation and subsequent pulmonary fibrosis. Herein we hypothesized that dedicator of cytokinesis 2 (DOCK2) promotes a proinflammatory phenotype of lung fibroblasts (LFs) to elicit lung injury and fibrosis in chronic HFHF diet–induced obesity. An HFHF diet for 20 weeks induced lung inflammation and profibrotic changes in wild-type C57BL/6 mice. CD68 and monocyte chemoattractant protein-1 (MCP-1) expression were notably increased in the lungs of wild-type mice fed an HFHF diet. An HFHF diet further increased lung DOCK2 expression that co-localized with fibroblast-specific protein 1, suggesting a role of DOCK2 in regulating proinflammatory phenotype of LFs. Importantly, DOCK2 knockout protected mice from lung inflammation and fibrosis induced by a HFHF diet. In primary human LFs, tumor necrosis factor-α (TNF-α) and IL-1β induced DOCK2 expression concurrent with MCP-1, IL-6, and matrix metallopeptidase 2. DOCK2 knockdown suppressed TNF-α–induced expression of these molecules and activation of phosphatidylinositol 3-kinase/AKT and NF-κB signaling pathways, suggesting a mechanism of DOCK2-mediated proinflammatory and profibrotic changes in human LFs. Taken together, these findings reveal a previously unrecognized role of DOCK2 in regulating proinflammatory phenotype of LFs, potentiation of lung inflammation, and pulmonary fibrosis in chronic HFHF diet–caused obesity.