Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Zhejiang Key Laboratory of Critical Care Medicine, Wenzhou, China; Wenzhou Key Laboratory of Critical Care and Artificial Intelligence, Wenzhou, China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167281. doi: 10.1016/j.bbadis.2024.167281. Epub 2024 Jun 12.
BACKGROUND & AIMS: Sepsis, a globally prevalent and highly lethal condition, remains a critical medical challenge. This investigation aims to assess the relevance of FGF1 as a potential therapeutic target for sepsis.
Sepsis was induced in C57BL/6 mice through LPS administration to establish an in vivo animal model. Various in vitro assays were conducted using human umbilical vein endothelial cells to elucidate the role of FGF1 in the disruption of the coagulation system and liver injury associated with sepsis, as well as to explore its underlying molecular mechanisms.
In in vivo experiments, FGF1 ameliorated coagulation system disruption in septic mice by reducing the levels of pro-inflammatory and coagulation-related factors in the bloodstream. FGF1 also enhanced liver function in septic mice, mitigating liver inflammation and cell apoptosis, fostering liver vascular regeneration, increasing liver blood perfusion, and improving mouse survival. In vitro experiments demonstrated that FGF1 could inhibit LPS-induced inflammatory responses and apoptosis in endothelial cells, fortify endothelial cell barrier function, decrease endothelial cell permeability, promote endothelial cell proliferation, and restore endothelial cell tube-forming ability. Both in vivo and in vitro experiments substantiated that FGF1 improved sepsis by inhibiting the IL-6/STAT3 signaling pathway.
In summary, our study indicates that FGF1 mitigates excessive inflammatory responses in sepsis by suppressing the IL-6/STAT3 signaling pathway, thereby improving systemic blood circulation and ameliorating liver damage in septic organisms. Consequently, this research identifies FGF1 as a potential clinical target for the treatment of human sepsis.
脓毒症是一种全球性普遍存在且致死率极高的疾病，仍是一个重大的医学挑战。本研究旨在评估 FGF1 作为脓毒症潜在治疗靶点的相关性。
通过 LPS 给药在 C57BL/6 小鼠中诱导脓毒症，建立体内动物模型。使用人脐静脉内皮细胞进行各种体外实验，以阐明 FGF1 在破坏脓毒症相关的凝血系统和肝损伤中的作用及其潜在的分子机制。
在体内实验中，FGF1 通过降低血液中促炎和凝血相关因子的水平，改善脓毒症小鼠的凝血系统紊乱。FGF1 还增强了脓毒症小鼠的肝功能，减轻了肝脏炎症和细胞凋亡，促进了肝脏血管再生，增加了肝脏血流灌注，并提高了小鼠的存活率。体外实验表明，FGF1 可抑制 LPS 诱导的内皮细胞炎症反应和细胞凋亡，增强内皮细胞屏障功能，降低内皮细胞通透性，促进内皮细胞增殖，并恢复内皮细胞管形成能力。体内和体外实验均证实，FGF1 通过抑制 IL-6/STAT3 信号通路改善了脓毒症。
综上所述，本研究表明，FGF1 通过抑制 IL-6/STAT3 信号通路减轻脓毒症中的过度炎症反应，从而改善全身血液循环并改善脓毒症机体的肝损伤。因此，该研究确定 FGF1 是治疗人类脓毒症的潜在临床靶点。
