Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China.
Department of Critical Care Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China.
Mol Med. 2023 Oct 25;29(1):144. doi: 10.1186/s10020-023-00714-6.
Ferroptosis plays an essential role in lipopolysaccharide (LPS)-induced acute lung injury (ALI). Meteorin-like/Meteorin-β (Metrnβ) is a protein secreted by skeletal muscle and adipose tissue and plays a role in cardiovascular diseases. However, its role in acute lung injury has not been elucidated.
In this study, we used an adenovirus (Ad) delivery system to overexpress or knockdown Metrnβ in lung tissue to examine the role of Metrnβ in LPS-induced acute lung injury.
We found that ferroptosis was increased during LPS-induced ALI. The expression of Metrnβ was reduced in ALI lung tissue. Overexpression of Metrnβ in lung tissue alleviated LPS-induced lung injury, inflammation, and ferroptosis. Moreover, Metrnβ knockout in lung tissue accelerated LPS-induced ALI, inflammation, and ferroptosis. We also cultured MLE-12 cells and transfected the cells with Ad-Metrnβ or Metrnβ siRNA. Metrnβ overexpression ameliorated LPS-induced MLE cell death, inflammation and ferroptosis, while Metrnβ knockdown aggregated cell survival and decreased inflammation and ferroptosis. Moreover, we found that Metrnβ enhanced ferroptosis-related Gpx4 expression and reduced ferroportin and ferritin levels. Furthermore, we found that Metrnβ positively regulated SIRT1 transcription thus inhibited P53, increased SLC7A11 expression. When we used the ferroptosis inhibitor ferrostatin-1, the deteriorating effects of Metrnβ knockout were abolished in ALI mice. Moreover, SIRT1 knockout also abolished the protective effects of Metrnβ overexpression in vivo.
Taken together, Metrnβ could protect LPS-induced ALI by activating SIRT1-P53- SLC7A11 mediated ferroptosis inhibition.
铁死亡在脂多糖（LPS）诱导的急性肺损伤（ALI）中起着至关重要的作用。Metrn 样/Meteorin-β（Metrnβ）是一种由骨骼肌和脂肪组织分泌的蛋白质，在心血管疾病中发挥作用。然而，其在急性肺损伤中的作用尚未阐明。
在本研究中，我们使用腺病毒（Ad）传递系统在肺组织中过表达或敲低 Metrnβ，以研究 Metrnβ在 LPS 诱导的急性肺损伤中的作用。
我们发现铁死亡在 LPS 诱导的 ALI 中增加。Metrnβ在 ALI 肺组织中的表达减少。肺组织中 Metrnβ的过表达减轻了 LPS 诱导的肺损伤、炎症和铁死亡。此外，肺组织中 Metrnβ的敲除加速了 LPS 诱导的 ALI、炎症和铁死亡。我们还培养了 MLE-12 细胞，并转染了 Ad-Metrnβ 或 Metrnβ siRNA。Metrnβ过表达改善了 LPS 诱导的 MLE 细胞死亡、炎症和铁死亡，而 Metrnβ 敲低则促进了细胞存活并减少了炎症和铁死亡。此外，我们发现 Metrnβ增强了铁死亡相关的 Gpx4 表达，降低了铁蛋白和铁蛋白水平。此外，我们发现 Metrnβ正向调节 SIRT1 转录，从而抑制 P53，增加 SLC7A11 表达。当我们使用铁死亡抑制剂 ferrostatin-1 时，在 ALI 小鼠中，Metrnβ 敲除的恶化作用被消除。此外，SIRT1 敲除也消除了 Metrnβ 过表达在体内的保护作用。
综上所述，Metrnβ 通过激活 SIRT1-P53-SLC7A11 介导的铁死亡抑制来保护 LPS 诱导的 ALI。
