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首页> 外文期刊>American Journal of Physiology >A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis.
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A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis.

机译：A3腺苷受体激活降低了鼠败血症性腹膜炎的死亡率以及肾脏和肝损伤。

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摘要

The role of A3 adenosine receptors (ARs) in sepsis and inflammation is controversial. In this study, we determined the effects of A3AR modulation on mortality and hepatic and renal dysfunction in a murine model of sepsis. To induce sepsis, congenic A3AR knockout mice (A3AR KO) and wild-type control (A3AR WT) mice were subjected to cecal ligation and double puncture (CLP). A3AR KO mice had significantly worse 7-day survival compared with A3AR WT mice. A3AR KO mice also demonstrated significantly higher elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and TNF-alpha 24 h after induction of sepsis compared with A3AR WT mice. Renal cortices from septic A3AR KO mice exhibited increased mRNA encoding proinflammatory cytokines and enhanced nuclear translocation of NF-kB compared with samples from A3AR WT mice. A3AR WT mice treated with N6-(3-iodobenzyl)ADO-5'N-methyluronamide (IB-MECA; a selective A3AR agonist) or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridi ne-3,5-dicarboxylate (MRS-1191; a selective A3AR antagonist) had improved or worsened 7-day survival after induction of sepsis, respectively. Moreover, A3AR WT mice treated with IB-MECA or MRS-1191 showed acutely improved or worsened, respectively, renal and hepatic function following CLP. IB-MECA significantly reduced mortality in mice lacking the A1AR or A2aAR but not the A3AR, demonstrating specificity of IB-MECA in activating A3ARs and mediating protection against sepsis-induced mortality. We conclude that endogenous or exogenous A3AR activation confers significant protection from murine septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
机译：A3腺苷受体（ARs）在脓毒症和炎症中的作用是有争议的。在这项研究中，我们确定了败血症小鼠模型中A3AR调节对死亡率以及肝肾功能障碍的影响。为了诱导败血症，对同基因A3AR基因敲除小鼠（A3AR KO）和野生型对照（A3AR WT）小鼠进行盲肠结扎和双穿刺（CLP）。与A3AR WT小鼠相比，A3AR KO小鼠的7天生存期明显更差。与脓毒症诱导后24小时相比，A3AR KO小鼠还显示血浆肌酐，丙氨酸转氨酶，天冬氨酸转氨酶，角化细胞衍生的趋化因子和TNF-α明显升高。与来自A3AR WT小鼠的样品相比，来自脓毒症A3AR KO小鼠的肾皮质显示出增加的编码促炎细胞因子的mRNA和增强的NF-kB核转运。用N6-（3-碘苄基）ADO-5'N-甲基脲酰胺（IB-MECA;选择性A3AR激动剂）或3-乙基-5-苄基-2-甲基-4-苯基乙炔基-6-苯基-治疗的A3AR WT小鼠1,4-（+/-）-二氢吡啶-3,5-二羧酸酯（MRS-1191;选择性A3AR拮抗剂）分别导致败血症诱发的7天生存期延长或恶化。此外，用IB-MECA或MRS-1191治疗的A3AR WT小鼠在CLP后分别表现出急性改善或恶化的肾和肝功能。 IB-MECA显着降低了缺乏A1AR或A2aAR而不是A3AR的小鼠的死亡率，这表明IB-MECA在激活A3ARs和介导败血症诱导的死亡率方面具有特异性。我们得出的结论是，内源性或外源性A3AR激活主要通过减轻脓毒症中的超急性炎症反应而赋予鼠类败血症性腹膜炎显着保护作用。

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