Effect of High Fat Diet on the Severity and Repair of Lung Fibrosis in Mice
Effect of High Fat Diet on the Severity and Repair of Lung Fibrosis in Mice
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DOI：
10.1089/scd.2021.0050
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发表时间：
2021-08-24
影响因子：
4
通讯作者：
Fukunaga, Koichi
中科院分区：
文献类型：
--
作者：
Hegab, Ahmed E.;Ozaki, Mari;Fukunaga, Koichi
肺纤维化是一种进行性致死性疾病，其发病机制尚不清楚。这些涉及改变的成纤维细胞、细胞外基质过度积累、炎症和上皮细胞异常活化的组合。以前，我们发现高脂饮食（HFD）诱导肺部炎症，干细胞异常激活和肺线粒体损伤。因此，我们假设HFD诱导的变化会影响肺纤维化。给小鼠喂食标准饮食（SD）或HFD，施用博来霉素，然后在损伤后3周检查纤维化严重程度和修复的开始，并在损伤后6 - 9周检查纤维化修复/消退。在3周时，在SD和HFD喂养的小鼠之间没有观察到炎症和纤维化严重程度的显著差异。然而，肺泡型（AT）-2细胞和细支气管肺泡干细胞（BASC）浸润到纤维化区域（修复的开始）在HFD喂养的小鼠中受损。在6周时，SD喂养的小鼠显示出纤维化和炎症的几乎完全消退/修复，而HFD喂养的小鼠仍显示出残留的纤维化和炎症。观察到AT2细胞浸润纤维化区域，但可检测到极少数BASC。在9周时，来自两组的小鼠显示出纤维化和炎症的完全消退/修复，表明HFD诱导纤维化和肺泡修复的延迟消退而不是失败消退。为了进一步证实增强的脂肪酸氧化（FAO）在延迟消退/修复中的直接作用，我们在博来霉素损伤后3 - 6周向HFD喂养的小鼠施用依托莫西（一种FAO抑制剂）。在两个时间点，抑制FAO消除了HFD诱导的肺泡修复和纤维化消退延迟。总之，在纤维化诱导损伤后，HFD通过减缓AT2干细胞的贡献并消除BASC在修复过程中的贡献来减缓纤维化/炎症的消退并延迟肺泡修复。FAO活化似乎参与了这种延迟机制;因此，抑制FAO可能有助于治疗肺损伤和纤维化。
Lung fibrosis is a progressive fatal disease, and the underlying mechanisms remain unclear. These involve a combination of altered fibroblasts, excessive accumulation of extracellular matrix, inflammation, and aberrant activation of epithelial cells. Previously, we showed that high-fat diet (HFD) induces lung inflammation, aberrant activation of stem cells, and lung mitochondria impairment. Therefore, we hypothesized that HFD-induced changes would influence lung fibrosis. Mice were fed standard diet (SD) or HFD, administered bleomycin, then examined for fibrosis severity and the start of repair 3 weeks after injury, and for fibrosis repair/resolution 6-9 weeks after injury. At 3 weeks, no significant differences in inflammation and fibrosis severity were observed between SD- and HFD-fed mice. However, infiltration of alveolar type (AT)-2 cells and bronchioalveolar stem cells (BASCs) into the fibrotic areas (the start of repair) was impaired in HFD-fed mice. At 6 weeks, SD-fed mice showed near-complete resolution/repair of fibrosis and inflammation, while HFD-fed mice still showed residual fibrosis and inflammation. Infiltration of the fibrotic areas with AT2 cells was observed, but very few BASCs were detectable. At 9 weeks, mice from both groups showed complete resolution/repair of fibrosis and inflammation, indicating that HFD induced delayed, rather than failed, resolution of fibrosis and alveolar repair. To further confirm the direct role of enhanced fatty-acid oxidation (FAO) in delayed resolution/repair, we administered etomoxir, a FAO inhibitor, to HFD-fed mice for 3-6 weeks after bleomycin injury. Inhibition of FAO abolished the HFD-induced delay in alveolar repair and fibrosis resolution at both time points. In conclusion, after a fibrosis-inducing injury, HFD slows resolution of fibrosis/inflammation and delays alveolar repair by slowing the contribution of AT2 stem cells and abolishing the contribution of BASCs in the repair process. FAO activation appears to be involved in this delay mechanism; thus, inhibiting FAO may be useful in the treatment of lung injury and fibrosis.