Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Department of Cardiovascular Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu 225300, China.
Int Immunopharmacol. 2024 Apr 20;131:111911. doi: 10.1016/j.intimp.2024.111911. Epub 2024 Mar 24.
Acute lung injury (ALI) has garnered significant attention in the field of respiratory and critical care due to its high mortality and morbidity, and limited treatment options. The role of the endothelial barrier in the development of ALI is crucial. Several bacterial pathogenic factors, including the bacteria-derived formyl peptide (fMLP), have been implicated in damaging the endothelial barrier and initiating ALI. However, the mechanism by which fMLP causes ALI remains unclear. In this study, we aim to explore the mechanisms of ALI caused by fMLP and evaluate the protective effects of MOTS-c, a mitochondrial-derived peptide.
We established a rat model of ALI and a human pulmonary microvascular endothelial cell (HPMVEC) model of ALI by treatment with fMLP. In vivo experiments involved lung histopathology assays, assessments of inflammatory and oxidative stress factors, and measurements of ferroptosis-related proteins and barrier proteins to evaluate the severity of fMLP-induced ALI and the type of tissue damage in rats. In vitro experiments included evaluations of fMLP-induced damage on HPMVEC using cell activity assays, assessments of inflammatory and oxidative stress factors, measurements of ferroptosis-related proteins, endothelial barrier function assays, and examination of the key role of FPR2 in fMLP-induced ALI. We also assessed the protective effect of MOTS-c and investigated its mechanism on the fMLP-induced ALI in vivo and in vitro.
Results from both in vitro and in vivo experiments demonstrate that fMLP promotes the expression of inflammatory and oxidative stress factors, activates ferroptosis and disrupts the vascular endothelial barrier, ultimately contributing to the development and progression of ALI. Mechanistically, ferroptosis mediated by FPR2 plays a key role in fMLP-induced injury, and the Nrf2 and MAPK pathways are involved in this process. Knockdown of FPR2 and inhibition of ferroptosis can attenuate ALI induced by fMLP. Moreover, MOTS-c could protect the vascular endothelial barrier function by inhibiting ferroptosis and suppressing the expression of inflammatory and oxidative stress factors through Nrf2 and MAPK pathways, thereby alleviating fMLP-induced ALI.
Overall, fMLP disrupts the vascular endothelial barrier through FPR2-mediated ferroptosis, leading to the development and progression of ALI. MOTS-c demonstrates potential as a protective treatment against ALI by alleviating the damage induced by fMLP.
急性肺损伤（ALI）因其高死亡率和发病率以及有限的治疗选择而在呼吸和危重病领域引起了极大关注。内皮屏障在 ALI 的发展中起着关键作用。几种细菌致病因子，包括细菌衍生的形式肽（fMLP），已被牵连到破坏内皮屏障并引发 ALI。然而，fMLP 引起 ALI 的机制尚不清楚。在这项研究中，我们旨在探讨 fMLP 引起的 ALI 的机制，并评估线粒体衍生肽 MOTS-c 的保护作用。
我们通过用 fMLP 处理建立了大鼠 ALI 模型和人肺微血管内皮细胞（HPMVEC）ALI 模型。体内实验涉及肺组织病理学检测、炎症和氧化应激因子评估以及铁死亡相关蛋白和屏障蛋白测量，以评估 fMLP 诱导的 ALI 的严重程度和大鼠的组织损伤类型。体外实验包括使用细胞活性测定评估 fMLP 对 HPMVEC 的损伤，评估炎症和氧化应激因子，测量铁死亡相关蛋白，内皮屏障功能测定，以及检查 FPR2 在 fMLP 诱导的 ALI 中的关键作用。我们还评估了 MOTS-c 的保护作用，并研究了其在体内和体外 fMLP 诱导的 ALI 中的作用机制。
体内和体外实验结果均表明，fMLP 促进炎症和氧化应激因子的表达，激活铁死亡并破坏血管内皮屏障，最终导致 ALI 的发生和发展。机制上，FPR2 介导的铁死亡在 fMLP 诱导的损伤中起关键作用，Nrf2 和 MAPK 途径参与了这一过程。FPR2 敲低和铁死亡抑制可减轻 fMLP 诱导的 ALI。此外，MOTS-c 通过抑制铁死亡和通过 Nrf2 和 MAPK 途径抑制炎症和氧化应激因子的表达来保护血管内皮屏障功能，从而缓解 fMLP 诱导的 ALI。
总之，fMLP 通过 FPR2 介导的铁死亡破坏血管内皮屏障，导致 ALI 的发生和发展。MOTS-c 通过减轻 fMLP 诱导的损伤，显示出作为 ALI 保护治疗的潜力。
