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.

中文翻译：

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高脂饮食对小鼠肺纤维化严重程度和修复的影响

肺纤维化是一种进行性致死性疾病，其潜在机制仍不清楚。这些包括改变的成纤维细胞、细胞外基质的过度积累、炎症和上皮细胞的异常活化。此前，我们发现高脂饮食 (HFD) 会诱导肺部炎症、干细胞异常激活和肺线粒体损伤。因此，我们假设 HFD 引起的变化会影响肺纤维化。给小鼠喂食标准饮食 (SD) 或 HFD，给予博莱霉素，然后在损伤后 3 周检查纤维化严重程度和修复开始，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着差异。然而，在 HFD 喂养的小鼠中，肺泡型 (AT)-2 细胞和支气管肺泡干细胞 (BASC) 向纤维化区域（修复开始）的浸润受损。在 6 周时，SD 喂养的小鼠表现出几乎完全的纤维化和炎症消退/修复，而 HFD 喂养的小鼠仍然表现出残留的纤维化和炎症。观察到 AT2 细胞浸润纤维化区域，但可检测到的 BASC 非常少。在 9 周时，两组小鼠的纤维化和炎症均完全消退/修复，表明 HFD 诱导了延迟而非失败的纤维化消退和肺泡修复。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，我们在博莱霉素损伤后对喂食HFD的小鼠施用了FAO抑制剂etomoxir 3-6周。在两个时间点，FAO 的抑制消除了 HFD 引起的肺泡修复和纤维化消退的延迟。总之，在纤维化诱导损伤后，HFD 通过减缓 AT2 干细胞的贡献和消除 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。粮农组织的启动似乎参与了这一延迟机制；因此，抑制FAO可能有助于治疗肺损伤和纤维化。