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The different effects of four adenosine receptors in liver fibrosis
Lan Yang1, Zhao-Wei Gao1, Xi Wang1
1Department of clinical diagnose, Tangdu hospital, Air Force Medical University, Xi'an, Shaanxi, China.
Background:
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.
Methods:
Intraperitoneal injection of CCl4 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).
Results:
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.
Conclusion:
This study demonstrated the different roles of A1R/A2AR/A2BR/A3R during liver fibrosis development via regulating the HSC activity and proliferation.
Insights
Adenosine receptors A1R and A2AR worsen liver fibrosis by promoting hepatic stellate cell activity, while A2BR and A3R agonists show protective effects. This highlights distinct therapeutic targets for liver fibrosis.
Area of Science:
- Immunology
- Pharmacology
- Hepatology
Background:
- The adenosine-adenosine receptor pathway is crucial in immune responses and inflammation.
- Four adenosine receptors (A1R, A2AR, A2BR, A3R) have distinct, sometimes opposing, roles in disease progression.
- Understanding these roles is vital for developing targeted liver fibrosis therapies.
Purpose of the Study:
- To investigate the specific roles of activating adenosine receptors A1R, A2AR, A2BR, and A3R in the context of liver fibrosis.
- To determine how these receptors influence hepatic stellate cell (HSC) activity and proliferation in liver fibrosis models.
Main Methods:
- Liver fibrosis was induced in C57BL/6 mice using CCl4.
- Specific agonists (CCPA, CGS21680, BAY 60-6583, namodenoson) were used to activate A1R, A2AR, A2BR, and A3R, respectively.
- Liver function (ALT, AST), histology (H&E, Masson, Sirius Red), and HSC behavior (CCK8, scratch assays, α-SMA, Col1α1 expression) were assessed.
Main Results:
- A1R and A2AR activation exacerbated liver fibrosis, increasing liver damage markers and collagen deposition.
- A2BR and A3R activation alleviated liver fibrosis, reducing damage and collagen.
- A1R/A2AR agonists enhanced HSC proliferation and migration, while A2BR/A3R agonists inhibited them. NECA also showed protective effects.
Conclusions:
- Adenosine receptors A1R and A2AR play a pro-fibrotic role by promoting HSC activity and proliferation.
- Adenosine receptors A2BR and A3R exhibit anti-fibrotic effects by inhibiting HSCs.
- Targeting specific adenosine receptors offers a potential therapeutic strategy for managing liver fibrosis.
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