School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
Respir Res. 2024 Feb 28;25(1):108. doi: 10.1186/s12931-024-02733-1.
Acute lung injury (ALI) is a devastating clinical disorder with a high mortality rate, and there is an urgent need for more effective therapies. Fibroblast growth factor 18 (FGF18) has potent anti-inflammatory properties and therefore has become a focus of research for the treatment of lung injury. However, the precise role of FGF18 in the pathological process of ALI and the underlying mechanisms have not been fully elucidated.
A mouse model of ALI and human umbilical vein endothelial cells (HUVEC) stimulated with lipopolysaccharide (LPS) was established in vivo and in vitro. AAV-FGF18 and FGF18 proteins were used in C57BL/6J mice and HUVEC, respectively. Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and p65 protein levels were determined by western blotting or immunofluorescent staining. Afterward, related inhibitors were used to explore the potential mechanism by which FGF18 relieves inflammation.
In this study, we found that FGF18 was significantly upregulated in LPS-induced ALI mouse lung tissues and LPS-stimulated HUVECs. Furthermore, our studies demonstrated that overexpressing FGF18 in the lung or HUVEC could significantly alleviate LPS-induced lung injury and inhibit vascular leakage.
Mechanically, FGF18 treatment dramatically inhibited the NF-κB signaling pathway both in vivo and in vitro. In conclusion, these results indicate that FGF18 attenuates lung injury, at least partially, via the NF-κB signaling pathway and therefore may be a potential therapeutic target for ALI.
急性肺损伤（ALI）是一种具有高死亡率的破坏性临床疾病，因此迫切需要更有效的治疗方法。成纤维细胞生长因子 18（FGF18）具有强大的抗炎特性，因此已成为治疗肺损伤的研究焦点。然而，FGF18 在 ALI 病理过程中的确切作用及其潜在机制尚未完全阐明。
在体内和体外建立了脂多糖（LPS）刺激的 ALI 小鼠模型和人脐静脉内皮细胞（HUVEC）。分别在 C57BL/6J 小鼠和 HUVEC 中使用 AAV-FGF18 和 FGF18 蛋白。通过 Western blot 或免疫荧光染色测定血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和 p65 蛋白水平。然后，使用相关抑制剂探讨 FGF18 缓解炎症的潜在机制。
本研究发现，FGF18 在 LPS 诱导的 ALI 小鼠肺组织和 LPS 刺激的 HUVEC 中均显著上调。此外，我们的研究表明，在肺部或 HUVEC 中过表达 FGF18 可显著减轻 LPS 诱导的肺损伤并抑制血管渗漏。
在体内和体外，FGF18 治疗均能显著抑制 NF-κB 信号通路。总之，这些结果表明 FGF18 通过 NF-κB 信号通路减轻肺损伤，至少部分减轻肺损伤，因此可能是 ALI 的潜在治疗靶点。
