热休克蛋白 110 通过促进 NF-κB 通路加重肝移植后的缺血再灌注损伤。

HSP110 aggravates ischemia-reperfusion injury after liver transplantation by promoting NF-κB pathway.

机构信息

Department of Hepatobiliary Surgery, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China.

Department of Cardiothoracic Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.

出版信息

Hepatobiliary Pancreat Dis Int. 2024 Aug;23(4):344-352. doi: 10.1016/j.hbpd.2023.08.012. Epub 2023 Aug 22.

DOI:10.1016/j.hbpd.2023.08.012

PMID:37648554

Abstract

BACKGROUND

Ischemia-reperfusion injury (IRI) poses a significant challenge to liver transplantation (LT). The underlying mechanism primarily involves overactivation of the immune system. Heat shock protein 110 (HSP110) functions as a molecular chaperone that helps stabilize protein structures.

METHODS

An IRI model was established by performing LT on Sprague-Dawley rats, and HSP110 was silenced using siRNA. Hematoxylin-eosin staining, TUNEL, immunohistochemistry, ELISA and liver enzyme analysis were performed to assess IRI following LT. Western blotting and quantitative reverse transcription-polymerase chain reaction were conducted to investigate the pertinent molecular changes.

RESULTS

Our findings revealed a significant increase in the expression of HSP110 at both the mRNA and protein levels in the rat liver following LT (P < 0.05). However, when rats were injected with siRNA-HSP110, IRI subsequent to LT was notably reduced (P < 0.05). Additionally, the levels of liver enzymes and inflammatory chemokines in rat serum were significantly reduced (P < 0.05). Silencing HSP110 with siRNA resulted in a marked decrease in M1-type polarization of Kupffer cells in the liver and downregulated the NF-κB pathway in the liver (P < 0.05).

CONCLUSIONS

HSP110 in the liver promotes IRI after LT in rats by activating the NF-κB pathway and inducing M1-type polarization of Kupffer cells. Targeting HSP110 to prevent IRI after LT may represent a promising new approach for the treatment of LT-associated IRI.

摘要

背景

缺血再灌注损伤（IRI）对肝移植（LT）构成重大挑战。其潜在机制主要涉及免疫系统的过度激活。热休克蛋白 110（HSP110）作为分子伴侣发挥作用，有助于稳定蛋白质结构。

方法

通过对 Sprague-Dawley 大鼠进行 LT 建立 IRI 模型，并使用 siRNA 沉默 HSP110。进行苏木精-伊红染色、TUNEL、免疫组织化学、ELISA 和肝酶分析，以评估 LT 后的 IRI。进行 Western blot 和定量逆转录聚合酶链反应，以研究相关分子变化。

结果

我们的研究结果显示，大鼠 LT 后肝内 HSP110 的 mRNA 和蛋白水平均显著升高（P < 0.05）。然而，当大鼠注射 siRNA-HSP110 时，LT 后继发的 IRI 明显减少（P < 0.05）。此外，大鼠血清中肝酶和炎症趋化因子的水平显著降低（P < 0.05）。用 siRNA 沉默 HSP110 导致肝内 Kupffer 细胞 M1 型极化明显减少，肝内 NF-κB 途径下调（P < 0.05）。