Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
Diagnostic Pathology Center, Fujian Medical University, Fuzhou 350122, China.
Int J Mol Sci. 2023 Jul 29;24(15):12180. doi: 10.3390/ijms241512180.
Kupffer cells (KCs) play a key part in the pathological process of acetaminophen (APAP)-induced acute liver injury (ALI), the leading cause of acute liver failure in the world. CXC motif chemokine ligand 5 (CXCL5) exerts proinflammatory effects in acute respiratory distress syndrome and arthritis. In the current study, we aim to reveal the effects of CXCL5 on the activation of KCs and the role of CXCL5 in the pathogenesis of APAP-induced hepatotoxicity. The in vivo study, conducted on mice intraperitoneally injected with APAP (300 mg/kg) to establish the ALI model and then treated with Anti-CXCL5 mAb at 30 min and 12 h after the APAP challenge, showed that CXCL5 expression significantly increased in injured livers, and Anti-CXCL5 mAb mitigated the degree of APAP-evoked ALI in mice which was proven through biochemicals and histological examination. Also, neutralization of CXCL5 had no significant effect on APAP metabolism in the liver but exhibited anti-inflammatory effects and ameliorated hepatocellular death in the injured liver. The in vitro data displayed that recombinant mouse CXCL5 treatment promoted APAP-induced cellular toxicity in primary hepatocytes co-cultured with KCs, compared with single-cultured hepatocytes. Consistent with the result, we found that the Anti-CXCL5 mAb gradient decreased LPS-induced expression of inflammatory cytokines in single-cultured KCs. Therefore, CXCL5 could stimulate KCs to produce inflammatory mediators, therefore damaging hepatocytes from APAP toxicity.
库普弗细胞（KCs）在对乙酰氨基酚（APAP）诱导的急性肝损伤（ALI）的病理过程中起着关键作用，APAP 是世界范围内急性肝衰竭的主要原因。CXC 基序趋化因子配体 5（CXCL5）在急性呼吸窘迫综合征和关节炎中发挥促炎作用。在本研究中，我们旨在揭示 CXCL5 对 KCs 激活的影响，以及 CXCL5 在 APAP 诱导的肝毒性发病机制中的作用。在体内研究中，我们通过给小鼠腹腔注射 APAP（300mg/kg）建立 ALI 模型，然后在 APAP 攻击后 30 分钟和 12 小时用抗-CXCL5 mAb 进行治疗，结果显示，CXCL5 在受损肝脏中的表达显著增加，抗-CXCL5 mAb 减轻了 APAP 诱发的小鼠 ALI 的严重程度，这通过生化和组织学检查得到了证实。此外，中和 CXCL5 对肝脏中的 APAP 代谢没有显著影响，但表现出抗炎作用并改善了受损肝脏中的肝细胞死亡。体外数据显示，与单独培养的肝细胞相比，重组小鼠 CXCL5 处理促进了与 KCs 共培养的原代肝细胞中 APAP 诱导的细胞毒性。与结果一致，我们发现，抗-CXCL5 mAb 梯度降低了 LPS 诱导的单独培养的 KCs 中炎症细胞因子的表达。因此，CXCL5 可以刺激 KCs 产生炎症介质，从而减轻 APAP 毒性对肝细胞的损伤。
