Purinergic P2X7 receptor blockade mitigates alcohol-induced steatohepatitis and intestinal injury by regulating MEK1/2-ERK1/2 signaling and egr-1 activity
| Autor: | Zhen-ni Liu, Lei-lei Ci, Qian-qian Su, Xiong-Wen Lv, Yang-yang Tian |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Alcoholic liver disease Pyridines MAP Kinase Kinase 2 Immunology MAP Kinase Kinase 1 Tetrazoles Inflammation Pharmacology Gut flora Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Rosaniline Dyes medicine Animals Humans Immunology and Allergy Early Growth Response Protein 1 Mitogen-Activated Protein Kinase 1 Liver injury Mitogen-Activated Protein Kinase 3 biology business.industry Purinergic receptor medicine.disease biology.organism_classification Gastrointestinal Microbiome Blockade Intestines Mice Inbred C57BL Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Purinergic P2Y Receptor Antagonists Cytokines medicine.symptom Steatohepatitis business Fatty Liver Alcoholic Signal Transduction |
| Zdroj: | International Immunopharmacology. 66:52-61 |
| ISSN: | 1567-5769 |
| DOI: | 10.1016/j.intimp.2018.11.012 |
| Popis: | The P2X7 receptor is an ATP-binding cation channel involved in a broad range of inflammatory diseases. However, little is known about the potential role of P2X7R in alcohol-induced steatohepatitis and intestinal injury. In our study, C57BL/6 mice were intraperitoneally injected with P2X7R antagonists Brilliant Blue G and A438079 from the 4th day to the 10th day during the induction of chronic plus binge alcohol feeding model. Our results showed that alcohol feeding induced significant steatohepatitis and liver injury, which were mitigated by P2X7R blockade as evidenced by decreased serum levels of ALT, AST, T-CHO and TG, reduced lipid accumulation, and less inflammation. The increased intestinal inflammatory cytokines production and the prominent intestinal barrier disruption caused by alcohol were also modulated by P2X7R antagonism. Interestingly, alcohol feeding increased the relative abundance of phylum Bacteroidetes while decreased the number of phylum Verrucomicrobia and genus Akkermansia in the cecal content, which were reversed by P2X7R antagonist. Importantly, the improvement of intestinal barrier function and the restoration of partial taxonomic alterations in the gut microbiota might contribute to protect the liver from gut microbiota dysbiosis-induced second hit. Furthermore, P2X7R blockade inhibited MEK1/2-ERK1/2 phosphorylation and egr-1 expression in both liver and intestine from alcohol-fed mice. Collectively, P2X7R blockade mitigates alcohol-induced steatohepatitis and intestinal injury by inhibiting MEK1/2-ERK1/2 signaling and egr-1 expression. These studies strongly suggest that P2X7R blockade may be a promising therapeutic approach for treating alcoholic liver disease. |
| Databáze: | OpenAIRE |
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