目的:慢性急性肝衰竭(ACLF)是一种短期死亡率高的综合征,仍然缺乏有效的干预措施。本研究旨在探讨小分子黄芩素能否缓解ACLF并阐明其分子机制。
方法:使用四氯化碳通过慢性肝损伤诱导ACLF小鼠模型,随后用脂多糖(LPS)诱导急性炎症。黄芩素通过腹腔注射给药,以探讨其治疗效果。体外实验利用iBMDM巨噬细胞系来研究潜在的机制。从临床ACLF患者收集外周血用于验证。
结果:在LPS诱导的ACLF小鼠模型中,黄芩素在急性炎症和肝脏损伤中表现出显著的减少,正如组织病理学评估所证明的那样,肝功能分析,和炎症标记物测量。转录组分析,加上分子生物学实验,发现黄芩素通过激活TrKB-CREB1信号轴来上调巨噬细胞上TREM2受体的表面表达,从而在ACLF中发挥作用。这促进了M2巨噬细胞极化并激活了细胞凋亡,从而抑制炎症和减轻肝损伤。此外,我们观察到术后外周血血浆可溶性TREM2(sTREM2)水平与炎症之间呈显著负相关,以及临床ACLF患者的不良结局。
结论:黄芩素通过增强巨噬细胞表面TREM2受体的表达,对ACLF具有保护作用,导致炎症的抑制,减轻肝脏损伤,和降低死亡率。此外,血浆sTREM2是预测ACLF患者不良结局的关键指标.
OBJECTIVE: Acute-on-chronic liver failure (ACLF) is a syndrome characterized by a high short-term mortality rate, and effective interventions are still lacking. This study aims to investigate whether the small molecule baicalein can mitigate ACLF and elucidate the molecular mechanisms.
METHODS: The ACLF mouse model was induced through chronic liver injury using carbon tetrachloride, followed by acute inflammation induction with lipopolysaccharide (LPS). Baicalein was administered through intraperitoneal injection to explore its therapeutic effects. In vitro experiments utilized the iBMDM macrophage cell line to investigate the underlying mechanisms. Peripheral blood was collected from clinical ACLF patients for validation.
RESULTS: In the LPS-induced ACLF mouse model, baicalein demonstrated a significant reduction in acute inflammation and liver damage, as evidenced by histopathological evaluation, liver function analysis, and inflammatory marker measurements. Transcriptomic analysis, coupled with molecular biology experiments, uncovered that baicalein exerts its effects in ACLF by activating the TrKB-CREB1 signaling axis to upregulate the surface expression of the TREM2 receptor on macrophages. This promotes M2 macrophage polarization and activates efferocytosis, thereby inhibiting inflammation and alleviating liver damage. Furthermore, we observed a substantial negative correlation between postoperative peripheral blood plasma soluble TREM2 (sTREM2) levels and inflammation, as well as adverse outcomes in clinical ACLF patients.
CONCLUSIONS: Baicalein plays a protective role in ACLF by enhancing the surface expression of the TREM2 receptor on macrophages, leading to the suppression of inflammation, mitigation of liver damage, and a reduction in mortality. Additionally, plasma sTREM2 emerges as a critical indicator for predicting adverse outcomes in ACLF patients.