Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Life Sci. 2023 Sep 1;328:121896. doi: 10.1016/j.lfs.2023.121896. Epub 2023 Jun 27.
The aim of this study was to explore the fibrogenic effects of ATP-P1Rs axis and ATP-P2Rs axis on alcohol-related liver fibrosis (ALF).
C57BL/6J CD73 knock out (KO) mice were used in our study. 8-12 weeks male mice were used as an ALF model in vivo. In conclusion, after one week of adaptive feeding, 5 % alcohol liquid diet was given for 8 weeks. High-concentration alcohol (31.5 %, 5 g/kg) was administered by gavage twice weekly, and 10 % CCl intraperitoneal injections (1 ml/kg) were administered twice weekly for the last two weeks. The mice in the control group were injected intraperitoneally with an equivalent volume of normal saline. Fasting for 9 h after the last injection, blood samples were collected, and related indicators were tested. In vitro, rat hepatic stellate cells (HSCs) were treated with 200 μM acetaldehyde to establish an alcoholic liver fibrosis for 48 h, then tested related indicators.
We found that both adenosine receptors including adenosine A, A, A, A receptors (AR, AR, AR, AR) and ATP receptors including P2X7, P2Y2 receptors (P2X7R, P2Y2R) were expressed increased in ALF. After CD73 was knocked out, we found that adenosine receptors expression decreased, ATP expression increased, and fibrosis degree decreased.
Based on the research, we discovered that adenosine plays a more important role in ALF. Therefore, blocking the ATP-P1Rs axis represented a potential treatment for ALF, and CD73 will become a potential therapeutic target.
本研究旨在探讨 ATP-P1Rs 轴和 ATP-P2Rs 轴对酒精性肝纤维化（ALF）的纤维生成作用。
本研究使用 C57BL/6J CD73 敲除（KO）小鼠。体内采用 8-12 周雄性小鼠作为 ALF 模型。总之，适应性喂养一周后，给予 5%酒精液体饮食 8 周。每周两次通过灌胃给予高浓度酒精（31.5%，5g/kg），最后两周每周两次给予 10% CCl 腹腔注射（1ml/kg）。对照组小鼠腹腔内注射等量生理盐水。最后一次注射后禁食 9 小时，采集血样，检测相关指标。体外，用 200μM 乙醛处理大鼠肝星状细胞（HSCs）建立酒精性肝纤维化 48 小时，然后检测相关指标。
我们发现，包括腺苷 A1、A2A、A2B 和 A3 受体（AR、AR、AR、AR）在内的腺苷受体和包括 P2X7、P2Y2 受体（P2X7R、P2Y2R）在内的 ATP 受体在 ALF 中表达增加。CD73 敲除后，我们发现腺苷受体表达减少，ATP 表达增加，纤维化程度降低。
基于这项研究，我们发现腺苷在 ALF 中发挥更重要的作用。因此，阻断 ATP-P1Rs 轴可能成为治疗 ALF 的一种潜在方法，CD73 将成为一个潜在的治疗靶点。
