Aim of the study

Acute lung injury (ALI) exhibits the features of noncardiogenic pulmonary edema and acute inflammatory process, and it also displays significant morbidity and mortality rates. This work focused on identifying how overexpression of PPARγ coactivator 1α (PGC-1α) positively regulated TFEB and mitophagy for resisting the lipopolysaccharide (LPS)-mediated ALI.

Materials and methods

The levels of autophagic proteins and inflammatory factors in LPS-induced ALI rats and primary type II alveolar epithelial cells were measured, respectively. Lung wet/dry ratios were calculated. Protein co-immunoprecipitation of PGC-1α and TFEB was detected. To explore the interaction between TFEB and PGC-1α, a luciferase reporter assay was conducted.

Results

The results showed that overexpression of PGC-1α decreases IL-1 and IL-6 but increases IL-10 in LPS-mediated ALI rats and type II alveolar epithelial cells (P < 0.05). Overexpression of PGC-1α can reduce lung edema in LPS-mediated ALI rats (P < 0.05). Overexpression of PGC-1α upregulates mitophagy-related proteins, such as TFEB, LC3B, Beclin, and LAMP1, and improves mitophagy in LPS-induced ALI. Protein immunoprecipitation indicated that TFEB and PGC-1α are interacting proteins. The luciferase reporter assay demonstrated that PGC-1α positively regulated TFEB in the LPS-induced primary type II alveolar epithelial cells.

Conclusion

PGC-1α protects LPS-induced ALI by decreasing inflammation and alleviating lung edema. The mechanism might be positive regulation of TFEB directly and then upregulation of mitophagy in LPS-induced ALI.

中文翻译：

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PGC-1α对TFEB和线粒体自噬的正向调节减轻LPS诱导的大鼠急性肺损伤

研究目的

急性肺损伤 (ALI) 表现出非心源性肺水肿和急性炎症过程的特征，并且还显示出显着的发病率和死亡率。这项工作的重点是确定 PPARγ 辅激活因子 1α (PGC-1α) 的过表达如何正向调节 TFEB 和线粒体自噬以抵抗脂多糖 (LPS) 介导的 ALI。

材料和方法

分别测量了 LPS 诱导的 ALI 大鼠和原代 II 型肺泡上皮细胞中自噬蛋白和炎症因子的水平。计算肺湿/干比。检测到 PGC-1α 和 TFEB 的蛋白质共免疫沉淀。为了探索 TFEB 和 PGC-1α 之间的相互作用，进行了荧光素酶报告基因检测。

结果

结果表明，在LPS介导的ALI大鼠和II型肺泡上皮细胞中，PGC-1α的过表达降低IL-1和IL-6，但增加IL-10（P  < 0.05）。PGC-1α过表达可减轻LPS介导的ALI大鼠肺水肿（P  < 0.05）。PGC-1α 的过表达上调线粒体自噬相关蛋白，如 TFEB、LC3B、Beclin 和 LAMP1，并改善 LPS 诱导的 ALI 中的线粒体自噬。蛋白质免疫沉淀表明 TFEB 和 PGC-1α 是相互作用的蛋白质。荧光素酶报告基因检测表明 PGC-1α 在 LPS 诱导的原代 II 型肺泡上皮细胞中正向调节 TFEB。

结论

PGC-1α 通过减少炎症和减轻肺水肿来保护 LPS 诱导的 ALI。其机制可能是直接正向调节 TFEB，然后在 LPS 诱导的 ALI 中上调线粒体自噬。