Adenosine A2A receptors play a role in the pathogenesis of hepatic cirrhosis
Adenosine A2A receptors play a role in the pathogenesis of hepatic cirrhosis
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DOI：
10.1038/sj.bjp.0706812
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发表时间：
2006-08-01
影响因子：
7.3
通讯作者：
Cronstein, Bruce N.
中科院分区：
文献类型：
--
作者：
Chan, Edwin S. L.;Montesinos, Maria Carmen;Cronstein, Bruce N.
1腺苷是一种有效的内源性炎症和组织修复调节剂。从受伤和缺氧组织中释放或响应毒素和药物的腺苷可能会诱导小鼠肺纤维化，推测是通过与特定的腺苷受体相互作用。因此，我们确定腺苷及其受体是否有助于肝纤维化的发病机制。2与其他组织和细胞类型一样，腺苷在体外响应于纤维化刺激物乙醇而释放（40 mg dl（-1））和甲氨蝶呤（100 nM）。3腺苷A（2A）受体在大鼠和人肝星状细胞系上表达，腺苷A2 A受体的占据促进这些细胞产生胶原蛋白。用肝毒素四氯化碳（CCl 4）处理的小鼠肝脏切片（0.05 ml油，50：50 v：v，皮下）和硫代乙酰胺（100 mg/kg PBS，腹腔注射）在体外培养时比未处理的小鼠释放更多的腺苷。4腺苷A（2A）受体缺陷型，但不是野生型或A（3）受体缺陷型，在CCl 4或硫代乙酰胺麻醉后，小鼠不会发生肝纤维化。5同样，咖啡因（50 mg/kg/天，po），一种非选择性腺苷受体拮抗剂，和ZM 241385（25 mg kg（-1）bid），一种选择性更强的腺苷A（2A）受体拮抗剂，减少暴露于CCl 4或硫代乙酰胺的野生型小鼠的肝纤维化。6这些结果表明，肝腺苷A（2A）受体在肝纤维化的发病机制中起积极作用，为肝硬化的防治提供了新的治疗靶点。
1 Adenosine is a potent endogenous regulator of inflammation and tissue repair. Adenosine, which is released from injured and hypoxic tissue or in response to toxins and medications, may induce pulmonary fibrosis in mice, presumably via interaction with a specific adenosine receptor. We therefore determined whether adenosine and its receptors contribute to the pathogenesis of hepatic fibrosis.2 As in other tissues and cell types, adenosine is released in vitro in response to the fibrogenic stimuli ethanol (40 mg dl(-1)) and methotrexate (100 nM).3 Adenosine A(2A) receptors are expressed on rat and human hepatic stellate cell lines and adenosine A2A receptor occupancy promotes collagen production by these cells. Liver sections from mice treated with the hepatotoxins carbon tetrachloride (CCl4) (0.05 ml in oil, 50 : 50 v : v, subcutaneously) and thioacetamide (100 mg kg(-1) in PBS, intraperitoneally) released more adenosine than those from untreated mice when cultured ex vivo.4 Adenosine A(2A) receptor-deficient, but not wild-type or A(3) receptor-deficient, mice are protected from development of hepatic fibrosis following CCl4 or thioacetamide exposure.5 Similarly, caffeine (50 mg kg(-1) day(-1), po), a nonselective adenosine receptor antagonist, and ZM241385 (25 mg kg(-1) bid), a more selective antagonist of the adenosine A(2A) receptor, diminished hepatic fibrosis in wild-type mice exposed to either CCl4 or thioacetamide.6 These results demonstrate that hepatic adenosine A(2A) receptors play an active role in the pathogenesis of hepatic fibrosis, and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis.