Yang Lan, Gao Zhao-Wei, Wang Xi, Wu Xia-Nan, Li Si-Min, Dong Ke, Zhu Xiao-Ming
Department of clinical diagnose, Tangdu hospital, Air Force Medical University, Xi'an, Shaanxi, China.
Department of Obstetrics and Gynecology, Hainan Branch of PLA General Hospital, Sanya, China.
Front Pharmacol. 2024 Sep 3;15:1424624. doi: 10.3389/fphar.2024.1424624. eCollection 2024.
The adenosine-adenosine receptor pathway plays important roles in the immune system and inflammation. Four adenosine receptors (i.e., A1R, A2AR, A2BR, and A3R) have been identified. However, the roles of these receptors were different in the disease progress and even play opposite roles in the same disease. This study aims to investigate the roles of A1R/A2AR/A2BR/A3R activation in liver fibrosis.
Intraperitoneal injection of CCl into C57BL/6 mice was used to induce liver fibrosis in the models. Adenosine receptor agonists CCPA, CGS21680, BAY 60-6583, and namodenoson were used for A1R/A2AR/A2BR/A3R activation, respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were used to evaluate the liver function. Hematoxylin and eosin (H&E) staining was used to investigate the pathological damage. Masson staining and Sirius Red staining were performed to evaluate the degree of collagen deposition. CCK8 and scratch assays were used to investigate the proliferation and migration ability of hepatic stellate cells (HSCs).
By using liver fibrosis mouse models, we observed that the A1R and A2AR agonists aggravated liver fibrosis, characterized by increasing ALT and AST levels, more serious liver pathological damage, and collagen deposition. However, the A2BR and A3R agonists alleviated liver fibrosis. Moreover, the A1R and A2AR agonist treatment promotes the proliferation and migration of HSC line LX2, while A2BR and A3R agonist treatment inhibited LX2 proliferation and migration. Consistently, A1R and A2AR agonist treatment elevated the expression of α-SMA and Col1α1 in LX2, whereas A2BR and A3R agonist treatment inhibited the expression of α-SMA and Col1α1 in LX2 cells. Additionally, 5'-N-ethyl-carboxamidoadenosine (NECA), a metabolically stable adenosine analog, alleviated liver fibrosis and inhibited LX2 cell activity, proliferation, and migration.
This study demonstrated the different roles of A1R/A2AR/A2BR/A3R during liver fibrosis development via regulating the HSC activity and proliferation.
腺苷-腺苷受体途径在免疫系统和炎症中发挥重要作用。已鉴定出四种腺苷受体（即A1R、A2AR、A2BR和A3R）。然而，这些受体在疾病进展中的作用不同，甚至在同一种疾病中发挥相反的作用。本研究旨在探讨A1R/A2AR/A2BR/A3R激活在肝纤维化中的作用。
通过向C57BL/6小鼠腹腔注射CCl诱导模型中的肝纤维化。分别使用腺苷受体激动剂CCPA、CGS21680、BAY 60-6583和namodenoson激活A1R/A2AR/A2BR/A3R。使用丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平评估肝功能。采用苏木精-伊红（H&E）染色观察病理损伤。进行Masson染色和天狼星红染色评估胶原沉积程度。使用CCK8和划痕试验研究肝星状细胞（HSCs）的增殖和迁移能力。
通过使用肝纤维化小鼠模型，我们观察到A1R和A2AR激动剂加重了肝纤维化，其特征是ALT和AST水平升高、更严重的肝脏病理损伤和胶原沉积。然而，A2BR和A3R激动剂减轻了肝纤维化。此外，A1R和A2AR激动剂处理促进了HSC系LX2的增殖和迁移，而A2BR和A3R激动剂处理抑制了LX2的增殖和迁移。一致地，A1R和A2AR激动剂处理提高了LX2中α-SMA和Col1α1的表达，而A2BR和A3R激动剂处理抑制了LX2细胞中α-SMA和Col1α1的表达。此外，5'-N-乙基-羧酰胺腺苷（NECA），一种代谢稳定的腺苷类似物，减轻了肝纤维化并抑制了LX2细胞活性、增殖和迁移。
本研究通过调节HSC活性和增殖证明了A1R/A2AR/A2BR/A3R在肝纤维化发展过程中的不同作用。
