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本帖最后由 StephenW 于 2019-8-4 21:24 编辑
Adenosinergic Signaling in Liver Fibrosis Shilpa Tiwari‐Heckler M.D.,
Z. Gordon Jiang M.D., Ph.D.
First published: 02 August 2019
https://doi.org/10.1002/cld.777
This study was supported by funding from the German Research Foundation (DFG grant TI 988/1‐1 to S.T.‐H.), the National Institute of Diabetes and Digestive and Kidney Diseases (grant K08DK115883 to Z.G.J.), the Alan Hofmann Clinical and Translational Research Award from American Association for the Study of Liver Diseases (to Z.G.J.), and the Clinical Research Award from the American College of Gastroenterology (to Z.G.J.).
Potential conflict of interest: Nothing to report.
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Abbreviations ADA adenosine deaminase ADP adenosine diphosphate AMP adenosine monophosphate ATP adenosine triphosphate ENT equilibrative nucleoside transporter IL‐12 interleukin‐12 TGF‐β transforming growth factor‐β TNF‐α tumor necrosis factor α
Liver fibrosis is the common pathway shared by various chronic liver diseases leading to liver failure and related complications. This process, characterized by an exaggerated and dysfunctional wound‐healing response, can result in a chronic tissue injury with an excessive deposition of extracellular matrix. It has become evident that fibrosis in the liver is mediated by concerted interplays between hepatic and nonhepatic cells. Several of these pathways are currently exploited for drug development. Despite the lack of US Food and Drug Administration–approved therapeutics that targets fibrogenesis at present, accumulating evidence indicates that drinking coffee is associated with a lower risk for liver fibrosis. Because caffeine is an adenosine antagonist, this raised the relevance of adenosinergic signaling in liver fibrosis.
Coffee is a widely consumed beverage worldwide. After the controversy of its cardiovascular implications settled in the 1970s, Arnesen et al.1 first reported an unexpected inverse association between serum gamma‐glutamyltransferase levels and coffee consumption in the Tromsø Heart Study in 1986. Since then, an array of epidemiological studies have reproduced similar beneficial associations of coffee in liver diseases, ranging from lower serum transaminase to reduced risks for advanced fibrosis in hepatitis C and nonalcoholic fatty liver disease, as well as mortalities in cirrhosis in general. These epidemiological associations have been well reviewed previously.2
Many have attributed the benefits of coffee to antioxidant properties of its distinctive compounds, such as polyphenols. The antioxidant hypothesis is appealing, but it is yet to be substantiated in the experimental setting. In contrast, growing evidence suggests that the mechanism of action by coffee could be directly linked to caffeine. In animal models of chemical‐induced liver fibrosis, caffeinated coffee more significantly protects against liver fibrosis than decaffeinated coffee.3
The biological activities of caffeine are likely driven by its impact on adenosinergic signaling. Adenosine is a potent extracellular purine metabolite that modulates inflammation, regeneration, and fibrosis.4 In the setting of cellular injury ranging from inflammation to hypoxia to apoptosis, adenosine triphosphate (ATP) is released into the extracellular milieu and converted to adenosine monophosphate (AMP) by ectoenzymes of the CD39 family, and AMP to adenosine via ecto‐5′‐nucleotidase, also known as CD73 (Fig. 1). Adenosine is further metabolized to inosine via one of the two adenosine deaminases (ADAs) or taken up back into the cell via equilibrate nucleoside transporter (ENT). While extracellular ATP signals through P2X or P2Y receptors, extracellular adenosine can activate one of the four G protein‐coupled receptors: A1, A2A, A2B, and A3. In a state of acute inflammation, adenosinergic signaling has anti‐inflammatory effects, whereas chronic exposure of adenosine may lead to fibrosis seen in various organs including the lung, kidney, and liver. In idiopathic pulmonary fibrosis, extracellular adenosine is causally linked to the progression of lung fibrosis, which can be ameliorated by reducing the extracellular adenosine level.5 Similarly, in chronic kidney disease, short‐term activation of A2A and A2B receptors decreases inflammation, whereas persistent exposure aggravates renal fibrosis in an A2B‐dependent manner.6
 Figure 1 Open in figure viewerPowerPoint
Signaling via extracellular purines and metabolites. ATP and adenosine diphosphate (ADP) are metabolized to AMP through CD39 family ectoenzymes. CD73 converts AMP to adenosine. Adenosine is irreversibly deaminated to inosine by the ectoenzyme ADA or transported back into the cell via ENT. Adenosine signaling is mediated via activation of four G protein‐coupled receptors.
In the liver, adenosine can impact liver fibrosis through several mechanisms. Genetic knockout studies in mouse models have provided significant insights in the differential roles of adenosine receptors in liver injuries.7 Among the four adenosine receptors, genetic depletion of A2A receptors had the most consistent antifibrotic benefit in various liver injury models. Adenosine directly impacts hepatic stellate cells (HSCs) via the A2A receptor and increases the production of type I and III collagen fibers (Fig. 2). In mice, pharmacological inhibition of A2A receptor reduces liver fibrosis in chemical‐induced liver injury models.8 Adenosine signaling also regulates the heterogeneity and differentiation of macrophages, the central immune regulator in the liver.9 The biological response to adenosine in macrophages is mediated by both A2A and A2B receptors (Fig. 2). On the one hand, A2A signaling mediates an anti‐inflammatory response by impairing the classical activation of macrophages and inhibiting the release of proinflammatory cytokines, such as tumor necrosis factor α (TNF‐α) and interleukin‐12 (IL‐12). On the other hand, the adenosinergic signaling through A2B receptors promotes an alternative activation of macrophages.10 One might postulate that the alternative activation of macrophages would promote tissue repair, and hence fibrosis. Nonetheless, evidence for such mechanism in humans remains lacking in part because of the plasticity of liver macrophages that often obscure the conventional division of classical (M1) and alternative (M2) phenotypes. It is now recognized that the human nonclassical CD14+CD16+ hepatic macrophages are strongly associated with fibrosis in patients with liver disease with various etiologies. It remains to be seen whether adenosine promotes the differentiation of this macrophage subpopulation.
 Figure 2 Open in figure viewerPowerPoint
Mechanism of adenosine in modulating liver fibrosis. Enhanced release of ATP during hepatocellular injury leads to an excess of adenosine in the hepatic extracellular milieu. Adenosine promotes liver fibrosis directly via activation of A2A receptors on HSCs leading to increased production of collagen fibers. Furthermore, adenosine signaling has an impact on the differentiation of macrophages by favoring the alternative activation via A2B receptors. Meanwhile, A2A receptor signaling inhibits the release of proinflammatory cytokines.
Research in the past two decades has observed a sizable benefit of caffeine and coffee against liver diseases in both preclinical and epidemiological studies. Underlying these observations is likely the nonselective antagonistic mechanism of caffeine on adenosinergic signaling. Causal evidence in forms of clinical trial is yet to be obtained. Although some have suggested the prescription of coffee for patients with chronic liver disease, we may someday translate experimental data to more specific therapeutic agents targeting the adenosinergic pathway.
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发表于 2019-8-4 21:21
