Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510665, China; The Third Clinical College of Southern Medical University, Guangzhou 510665, China.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
Biochem Pharmacol. 2023 Jul;213:115632. doi: 10.1016/j.bcp.2023.115632. Epub 2023 May 31.
Sepsis is a systemic inflammatory disease caused by multiple pathogens, with the most commonly affected organ being the lung. 3-Hydroxybutyrate plays a protective role in inflammatory diseases through autophagy promotion; however, the exact mechanism remains unexplored.
Our study used the MIMIC-III database to construct a cohort of ICU sepsis patients and figure out the correlation between the level of ketone bodies and clinical prognosis in septic patients. In vivo and in vitro models of sepsis were used to reveal the role and mechanism of 3-hydroxybutyrate in sepsis-associated acute lung injury (sepsis-associated ALI).
Herein, we observed a strong correlation between the levels of ketone bodies and clinical prognosis in patients with sepsis identified using the MIMIC- III database. In addition, exogenous 3-hydroxybutyrate supplementation improved the survival rate of CLP-induced sepsis in mice by promoting autophagy. Furthermore, 3-hydroxybutyrate treatment protected against sepsis-induced lung damage. We explored the mechanism underlying these effects. The results indicated that 3-hydroxybutyrate upregulates autophagy levels by promoting the transfer of transcription factor EB (TFEB) to the macrophage nucleus in a G-protein-coupled receptor 109 alpha (GPR109α) dependent manner, upregulating the transcriptional level of ultraviolet radiation resistant associated gene (UVRAG) and increasing the formation of autophagic lysosomes.
3-Hydroxybutyrate can serve as a beneficial therapy for sepsis-associated ALI through the upregulation of autophagy. These results may provide a basis for the development of promising therapeutic strategies for sepsis-associated ALI.
败血症是一种由多种病原体引起的系统性炎症性疾病，最常受累的器官是肺。3-羟丁酸通过促进自噬在炎症性疾病中发挥保护作用；然而，其确切机制尚不清楚。
我们的研究使用 MIMIC-III 数据库构建了一个 ICU 败血症患者队列，并确定了脓毒症患者中酮体水平与临床预后的相关性。我们使用体内和体外败血症模型揭示了 3-羟丁酸在脓毒症相关急性肺损伤（sepsis-associated ALI）中的作用和机制。
在此，我们观察到使用 MIMIC-III 数据库确定的败血症患者的酮体水平与临床预后之间存在很强的相关性。此外，外源性 3-羟丁酸补充通过促进自噬提高 CLP 诱导的脓毒症小鼠的存活率。此外，3-羟丁酸治疗可防止脓毒症引起的肺损伤。我们探讨了这些作用的机制。结果表明，3-羟丁酸通过 G 蛋白偶联受体 109α（GPR109α）依赖性方式促进转录因子 EB（TFEB）向巨噬细胞核内转移，从而上调自噬水平，上调紫外线辐射抗性相关基因（UVRAG）的转录水平，并增加自噬溶酶体的形成。
3-羟丁酸可通过上调自噬作为治疗脓毒症相关 ALI 的有益疗法。这些结果可能为开发治疗脓毒症相关 ALI 的有前途的治疗策略提供依据。
