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 1Open 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 2Open 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.
作者: StephenW 时间: 2019-8-4 21:22
肝纤维化中的腺苷能信号
Shilpa Tiwari-Heckler M.D.，
Z. Gordon Jiang M.D.，Ph.D。
首次发表：2019年8月2日 Https://doi.org/10.1002/cld.777
这项研究得到了德国研究基金会（DFG资助TI 988 / 1-1至ST-H。），国家糖尿病和消化和肾脏疾病研究所（授予K08DK115883至ZGJ），Alan Hofmann临床和转化的资助。美国肝病研究协会（至ZGJ）的研究奖，以及美国胃肠病学会（至ZGJ）的临床研究奖。
潜在的利益冲突：无需报告。
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缩略语
ADA
腺苷脱氨酶
ADP
腺苷二磷酸
AMP
腺苷一磷酸
ATP
三磷酸腺苷
耳鼻喉科
平衡核苷转运蛋白
IL-12
白细胞介素12
TGF-β
转化生长因子-β
TNF-α
肿瘤坏死因子α
咖啡因的生物活性可能是由其对腺苷能信号传导的影响所驱动的。腺苷是一种有效的细胞外嘌呤代谢物，可调节炎症，再生和纤维化.4在从炎症到缺氧到细胞凋亡的细胞损伤环境中，三磷酸腺苷（ATP）被释放到细胞外环境中并转化为腺苷一磷酸（AMP）通过CD39家族的ectoenzymes和通过ecto-5'-核苷酸酶（也称为CD73）对腺苷的AMP（图1）。腺苷通过部分a a a a a a a a a a a a a a a a a，a A A，A2 B和A a进一步代谢为肌苷。在急性炎症状态下，腺苷能信号传导具有抗炎作用，这种腺苷的长期暴露可能导致在包括肺，肾和肝在内的各种器官中看到的纤维化。在特发性肺纤维化中，细胞外腺苷与肺纤维化的进展密切相关，可通过降低细胞外腺苷水平来改善.5类似，在慢性肾病中，A2A和A2B受体的短期活化减少炎症，高于持续性暴露加重了A2B依赖性肾纤维化
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图1
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通过细胞外嘌呤和代谢物发出信号。 ATP和二磷酸腺苷（ADP）通过CD39家族胞外酶代谢为AMP。 CD73将AMP转化为腺苷。腺苷通过胞外酶ADA不可逆地脱氨基至肌苷，或通过ENT转运回细胞。腺苷信号传导是通过激活四种G蛋白偶联受体介导的。
在肝脏中，腺苷可通过几种机制影响肝纤维化。小鼠模型中的基因敲除研究为腺苷受体在肝损伤中的不同作用提供了重要的见解.7在四种腺苷受体中，A2A受体的遗传耗竭在各种肝损伤模型中具有最一致的抗纤维化益处。腺苷通过A2A受体直接影响肝星状细胞（HSC），并增加I型和III型胶原纤维的产生（图2）。在小鼠中，A2A受体的药理学抑制减少了化学诱导的肝损伤模型中的肝纤维化.8腺苷信号传导还调节肝脏中央免疫调节因子巨噬细胞的异质性和分化.9巨噬细胞中腺苷的生物学反应是由A2A和A2B受体（图2）。一方面，A2A信号通过损害巨噬细胞的经典活化和抑制促炎细胞因子（例如肿瘤坏死因子α（TNF-α）和白细胞介素-12（IL-12））的释放来介导抗炎反应。另一方面，通过A2B受体的腺苷能信号传导促进了巨噬细胞的另一种活化。人们可能假定巨噬细胞的替代激活会促进组织修复，从而促进纤维化。尽管如此，人体中这种机制的证据仍然缺乏，部分原因是肝脏巨噬细胞的可塑性常常模糊了传统（M1）和替代（M2）表型的常规划分。现在认识到人类非经典CD14 + CD16 +肝巨噬细胞与患有各种病因的肝病患者的纤维化强烈相关。腺苷是否促进该巨噬细胞亚群的分化还有待观察。
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图2
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腺苷调节肝纤维化的机制。在肝细胞损伤期间ATP的增强释放导致肝细胞外环境中过量的腺苷。腺苷通过激活HSC上的A2A受体直接促进肝纤维化，导致胶原纤维的产生增加。此外，腺苷信号传导通过有利于通过A2B受体的替代活化而影响巨噬细胞的分化。同时，A2A受体信号传导抑制促炎细胞因子的释放。
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Figure 2 Open in figure viewerPowerPoint