Institute for Liver Diseases of Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China; Department of Pharmacy, Anhui Provincial Cancer Hospital, West Branch of The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230031, China.
Institute for Liver Diseases of Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, China.
Int Immunopharmacol. 2022 Aug;109:108909. doi: 10.1016/j.intimp.2022.108909. Epub 2022 Jun 11.
Inflammation plays an important role in the progression of alcohol-related liver disease (ALD). UDP-P2Y signaling is involved in many human diseases. The purinergic P2Y receptor, an important regulator of inflammation and phagocytosis, has attracted attention, but its role in alcoholic steatohepatitis remains unclear. Here, we found that P2Y levels were significantly elevated in Kupffer cells in the livers of mice with alcoholic steatohepatitis and ethanol (EtOH)-induced RAW264.7 cells. In this study, mice with alcoholic steatohepatitis were intraperitoneally injected with MRS2578, a specific inhibitor of the P2Y receptor, and P2Y was silenced in EtOH-induced RAW264.7 cells. We found a marked improvement in steatosis and inflammation in the livers of mice with alcoholic steatohepatitis and EtOH-induced RAW264.7 cells. However, P2Y activation in vivo and overexpression in vitro showed contrasting results. In addition, the expression of phospho-p38 mitogen-activated protein kinase (p-p38 MAPK), a phosphorylated protein in the p38 MAPK signaling pathway, was significantly altered after P2Y silencing or overexpression in vitro. P2Y can induce the activation of the p38 MAPK signaling pathway by mediating the calcium influx, whereas inhibition of the expression of P2Y can block the inflammatory process to some extent and thus improve the inflammatory response. The results of this study suggested that targeting P2Y signaling may be a potentially effective strategy for the treatment of alcoholic steatohepatitis.
炎症在酒精性肝病 (ALD) 的进展中起着重要作用。UDP-P2Y 信号参与许多人类疾病。嘌呤能 P2Y 受体是炎症和吞噬作用的重要调节剂，已引起关注，但它在酒精性脂肪性肝炎中的作用尚不清楚。在这里，我们发现酒精性脂肪性肝炎小鼠肝脏中的库普弗细胞和乙醇 (EtOH) 诱导的 RAW264.7 细胞中 P2Y 水平显著升高。在这项研究中，用 P2Y 受体的特异性抑制剂 MRS2578 腹腔注射酒精性脂肪性肝炎小鼠，并在 EtOH 诱导的 RAW264.7 细胞中沉默 P2Y。我们发现，酒精性脂肪性肝炎小鼠和 EtOH 诱导的 RAW264.7 细胞的肝脏脂肪变性和炎症明显改善。然而，体内 P2Y 的激活和体外的过表达表现出相反的结果。此外，在体外沉默或过表达 P2Y 后，p38 丝裂原活化蛋白激酶 (p38 MAPK) 信号通路中磷酸化蛋白 p-p38 MAPK 的表达也发生了显著改变。P2Y 通过介导钙内流来诱导 p38 MAPK 信号通路的激活，而抑制 P2Y 的表达在一定程度上可以阻断炎症过程，从而改善炎症反应。这项研究的结果表明，靶向 P2Y 信号可能是治疗酒精性脂肪性肝炎的一种潜在有效策略。
