Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
Pathol Res Pract. 2022 Aug;236:153979. doi: 10.1016/j.prp.2022.153979. Epub 2022 Jun 15.
Liver injury is the main factor in multiple organ failure caused by sepsis. Thymic stromal lymphopoietin (TSLP) is derived from epithelial cells and plays an important role in inflammation, allergies and cancer. The role of TSLP in sepsis-induced liver injury (SILI) is unclear. The purpose of this study was to investigate the effect of TSLP on sepsis-induced liver injury and to clarify the mechanism.
Wild-type (WT) mice and TSLPR knockout (TSLPR) mice were subjected to cecal ligation and puncture (CLP) to generate a SILI model. Liver injury was assessed by measuring the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), histologic liver injury scores, hepatocyte death, and liver inflammatory factors. Signal pathways were explored in vivo to identify possible mechanisms for TSLP in SILI.
The expression of TSLP and TSLPR increased during SILI. Deletion of TSLPR exacerbated liver injury in terms of serum ALT, AST, histologic liver injury scores, and liver inflammatory factors. Compared with controls, administration of exogenous recombinant mouse TSLP reduced liver injury in WT mice during SILI, but failed to reduce liver injury in TSLPR mice. TSLP induced autophagy in hepatocytes during SILI. Mechanistically, Akt and STAT3 were activated in WT mice during SILI. The opposite results were observed in TSLPR mice. In addition, the protective effects of TSLP in WT mice were blocked by PI3K inhibitor, LY294002, during SILI.
These results suggest that TSLP can improve liver injury caused by sepsis and its specific mechanism may be related to inducing autophagy through the PI3K/Akt/STAT3 signaling pathway.
肝脏损伤是脓毒症引起多器官衰竭的主要因素。胸腺基质淋巴细胞生成素（TSLP）来源于上皮细胞，在炎症、过敏和癌症中发挥重要作用。TSLP 在脓毒症诱导的肝损伤（SILI）中的作用尚不清楚。本研究旨在探讨 TSLP 对脓毒症诱导的肝损伤的影响，并阐明其机制。
野生型（WT）小鼠和 TSLPR 敲除（TSLPR）小鼠接受盲肠结扎穿孔（CLP）以产生 SILI 模型。通过测量血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、组织学肝损伤评分、肝细胞死亡和肝炎症因子来评估肝损伤。在体内探索信号通路，以确定 TSLP 在 SILI 中的可能机制。
在 SILI 期间，TSLP 和 TSLPR 的表达增加。TSLPR 缺失加剧了 SILI 中的肝损伤，表现在血清 ALT、AST、组织学肝损伤评分和肝炎症因子方面。与对照组相比，在 SILI 期间，外源性重组小鼠 TSLP 减轻了 WT 小鼠的肝损伤，但未能减轻 TSLPR 小鼠的肝损伤。在 SILI 期间，TSLP 诱导了肝细胞自噬。机制上，在 SILI 期间 WT 小鼠中的 Akt 和 STAT3 被激活。在 TSLPR 小鼠中观察到相反的结果。此外，在 SILI 期间，PI3K 抑制剂 LY294002 阻断了 TSLP 在 WT 小鼠中的保护作用。
这些结果表明，TSLP 可以改善脓毒症引起的肝损伤，其特定机制可能与通过 PI3K/Akt/STAT3 信号通路诱导自噬有关。
