Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis.
Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis.
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DOI：
10.1371/journal.pone.0069114
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Nagy LE
中科院分区：
文献类型：
--
作者：
Chiang DJ;Roychowdhury S;Bush K;McMullen MR;Pisano S;Niese K;Olman MA;Pritchard MT;Nagy LE
中度饮酒对肝纤维化的影响尚不清楚，但有证据表明腺苷可能在中度酒精对组织损伤的介导作用中发挥作用。乙醇增加肝脏中腺苷的浓度。已知腺苷2A受体（A2AR）激活可增强肝星状细胞（HSC）激活，并且A2AR缺陷小鼠可保护小鼠免于纤维化。利用适度乙醇消耗的新型小鼠模型，雌性C57BL/6J小鼠被允许继续获得2% （vol/vol）乙醇（11%卡路里）或配对喂养的对照饮食2天，2周或5周，并叠加暴露于CCl4，我们验证了这样的假设，即适度的乙醇消耗增加了四氯化碳（CCl4）的纤维化反应，并用A2AR拮抗剂治疗小鼠可以预防和/或逆转乙醇诱导的肝纤维化增加。乙醇不影响CCl4生物活化所需的CYP2E1的表达和活性，也不影响血浆中AST和ALT的活性，说明适量乙醇不增加CCl4的直接肝毒性。然而，暴露于CCl4后，乙醇喂养增强了HSC的激活并加剧了肝纤维化。这与肝窦血管生成反应增加有关。用A2AR拮抗剂治疗可以预防和逆转乙醇加剧肝纤维化的能力。适度的乙醇消耗会加剧暴露于CCl4后的肝纤维化。A2AR拮抗剂可能是一种潜在的药物干预，以减少对乙醇反应的肝纤维化。
The effect of moderate alcohol consumption on liver fibrosis is not well understood, but evidence suggests that adenosine may play a role in mediating the effects of moderate ethanol on tissue injury. Ethanol increases the concentration of adenosine in the liver. Adenosine 2A receptor (A2AR) activation is known to enhance hepatic stellate cell (HSC) activation and A2AR deficient mice are protected from fibrosis in mice. Making use of a novel mouse model of moderate ethanol consumption in which female C57BL/6J mice were allowed continued access to 2% (vol/vol) ethanol (11% calories) or pair-fed control diets for 2 days, 2 weeks or 5 weeks and superimposed with exposure to CCl4, we tested the hypothesis that moderate ethanol consumption increases fibrosis in response to carbon tetrachloride (CCl4) and that treatment of mice with an A2AR antagonist prevents and/or reverses this ethanol-induced increase in liver fibrosis. Neither the expression or activity of CYP2E1, required for bio-activation of CCl4, nor AST and ALT activity in the plasma were affected by ethanol, indicating that moderate ethanol did not increase the direct hepatotoxicity of CCl4. However, ethanol feeding enhanced HSC activation and exacerbated liver fibrosis upon exposure to CCl4. This was associated with an increased sinusoidal angiogenic response in the liver. Treatment with A2AR antagonist both prevented and reversed the ability of ethanol to exacerbate liver fibrosis. Moderate ethanol consumption exacerbates hepatic fibrosis upon exposure to CCl4. A2AR antagonism may be a potential pharmaceutical intervention to decrease hepatic fibrosis in response to ethanol.
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影响因子：
7.3
作者：
Chan, Edwin S. L.;Montesinos, Maria Carmen;Cronstein, Bruce N.
通讯作者：
Cronstein, Bruce N.
影响因子：
29.4
作者：
Carini, R;De Cesaris, MG;Albano, E
通讯作者：
Albano, E
影响因子：
29.4
作者：
McMullen, MR;Pritchard, MT;Nagy, LE
通讯作者：
Nagy, LE
影响因子：
--
作者：
ASHLEY, MJ;OLIN, JS;RANKIN, JG
通讯作者：
RANKIN, JG
影响因子：
6
作者：
Montesinos, MC;Desai, A;Cronstein, BN
通讯作者：
Cronstein, BN