Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Road (No.2), Huangpu District, Shanghai, 200025, P.R. China.
The first rehabilitation hospital of Shandong, Linyi, 276000, Shandong, P.R. China.
Respir Res. 2024 May 9;25(1):201. doi: 10.1186/s12931-024-02824-z.
Growth differentiation factor 15 (GDF15) as a stress response cytokine is involved in the development and progression of several diseases associated with metabolic disorders. However, the regulatory role and the underlying mechanisms of GDF15 in sepsis remain poorly defined. Our study analyzed the levels of GDF15 and its correlations with the clinical prognosis of patients with sepsis. In vivo and in vitro models of sepsis were applied to elucidate the role and mechanisms of GDF15 in sepsis-associated lung injury. We observed strong correlations of plasma GDF15 levels with the levels of C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), and lactate as well as Sequential Organ Failure Assessment (SOFA) scores in patients with sepsis. In the mouse model of lipopolysaccharide-induced sepsis, recombinant GDF15 inhibited the proinflammatory responses and alleviated lung tissue injury. In addition, GDF15 decreased the levels of cytokines produced by alveolar macrophages (AMs). The anti-inflammatory effect of glycolysis inhibitor 2-DG on AMs during sepsis was mediated by GDF15 via inducing the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) and the expression of activating transcription factor 4 (ATF4). Furthermore, we explored the mechanism underlying the beneficial effects of GDF15 and found that GDF15 inhibited glycolysis and mitogen-activated protein kinases (MAPK)/nuclear factor-κB (NF-κB) signaling via promoting AMPK phosphorylation. This study demonstrated that GDF15 inhibited glycolysis and NF-κB/MAPKs signaling via activating AMP-activated protein kinase (AMPK), thereby alleviating the inflammatory responses of AMs and sepsis-associated lung injury. Our findings provided new insights into novel therapeutic strategies for treating sepsis.
生长分化因子 15（GDF15）作为一种应激反应细胞因子，参与了多种与代谢紊乱相关疾病的发生和发展。然而，GDF15 在脓毒症中的调节作用和潜在机制仍未得到明确界定。本研究分析了 GDF15 的水平及其与脓毒症患者临床预后的相关性。应用体内和体外脓毒症模型阐明了 GDF15 在脓毒症相关肺损伤中的作用和机制。我们观察到脓毒症患者血浆 GDF15 水平与 C 反应蛋白（CRP）、降钙素原（PCT）、乳酸脱氢酶（LDH）和乳酸水平以及序贯器官衰竭评估（SOFA）评分呈强相关性。在脂多糖诱导的脓毒症小鼠模型中，重组 GDF15 抑制了促炎反应并减轻了肺组织损伤。此外，GDF15 降低了肺泡巨噬细胞（AMs）产生的细胞因子水平。在脓毒症期间，糖酵解抑制剂 2-DG 通过诱导真核起始因子 2（eIF2α）α 亚基磷酸化和激活转录因子 4（ATF4）的表达来介导 GDF15 对 AMs 的抗炎作用。此外，我们探讨了 GDF15 有益作用的机制，发现 GDF15 通过促进 AMPK 磷酸化抑制糖酵解和丝裂原激活蛋白激酶（MAPK）/核因子-κB（NF-κB）信号通路。本研究表明，GDF15 通过激活 AMP 激活蛋白激酶（AMPK）抑制糖酵解和 NF-κB/MAPKs 信号通路，从而减轻 AMs 的炎症反应和脓毒症相关的肺损伤。我们的研究结果为治疗脓毒症的新治疗策略提供了新的见解。
