P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice
P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice
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DOI：
10.1152/ajpgi.00352.2011
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发表时间：
2012-05-01
影响因子：
4.5
通讯作者：
Mehal, Wajahat Z.
中科院分区：
文献类型：
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作者：
Hoque, Rafaz;Sohail, Muhammed Adnan;Mehal, Wajahat Z.
Hoque R，Sohail MA，Salhanick S，Malik AF，Ghani A，Robson SC，Mehal WZ. P2 x7受体介导的嘌呤能信号促进对乙酰氨基酚肝毒性小鼠的肝损伤。美国生理学杂志胃肠和肝脏生理学302：G1171-G1179，2012年。首次发表于2012年3月1日; doi：10.1152/ajpgi.00352.2011。炎症导致对乙酰氨基酚（APAP）肝毒性小鼠的肝损伤，并由免疫细胞的刺激引发。嘌呤能受体P2 X7是免疫细胞中的类P2 X3受体家族的上游，含有Pryin结构域的3（NLRP 3）炎性体，并被作为损伤相关分子模式的ATP和NAD激活。在遗传缺陷P2 X7（核苷酸的关键炎症受体（P2 X7-/-））的小鼠和野生型小鼠中评估APAP肝毒性。P2 X7-/-小鼠显著减少APAP诱导的肝坏死。此外，APAP中毒的小鼠用特异性P2 X7拮抗剂A438079或NAD的竞争性拮抗剂Etheno-NAD治疗。用A438079预处理或后处理显著减少野生型但不是P2 X7-/-小鼠中APAP肝损伤中APAP诱导的坏死和出血。在APAP肝损伤中，用乙烯基NAD预处理也显著减少APAP诱导的坏死和出血。此外，在缺乏代谢ATP的质膜ectoNTPD酶CD 39（CD 39-/-）的小鼠中，APAP毒性与使用可溶性腺苷三磷酸双磷酸酶消耗野生型小鼠中的细胞外ATP平行检查。CD 39-/-小鼠增加了APAP诱导的出血和死亡率，而腺苷三磷酸双磷酸酶也降低了APAP诱导的死亡率。用细胞外ATP处理枯否细胞以评估P2 X7依赖性炎性小体活化。P2 X7是ATP刺激的IL-1 β释放所必需的。总之，P2 X7和暴露于配体ATP和NAD是APAP诱导的肝毒性表现所需的。
Hoque R, Sohail MA, Salhanick S, Malik AF, Ghani A, Robson SC, Mehal WZ. P2x7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice. Am J Physiol Gastrointest Liver Physiol 302: G1171-G1179, 2012. First published March 1, 2012; doi:10.1152/ajpgi.00352.2011.-Inflammation contributes to liver injury in acetaminophen (APAP) hepatotoxicity in mice and is triggered by stimulation of immune cells. The purinergic receptor P2X7 is upstream of the nod-like receptor family, pryin domain containing-3 (NLRP3) inflammasome in immune cells and is activated by ATP and NAD that serve as damage-associated molecular patterns. APAP hepatotoxicity was assessed in mice genetically deficient in P2X7, the key inflammatory receptor for nucleotides (P2X7-/-), and in wild-type mice. P2X7-/- mice had significantly decreased APAP-induced liver necrosis. In addition, APAP-poisoned mice were treated with the specific P2X7 antagonist A438079 or etheno-NAD, a competitive antagonist of NAD. Pre-or posttreatment with A438079 significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury in wild-type but not P2X7-/- mice. Pretreatment with etheno-NAD also significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury. In addition, APAP toxicity in mice lacking the plasma membrane ectoNTPDase CD39 (CD39-/-) that metabolizes ATP was examined in parallel with the use of soluble apyrase to deplete extracellular ATP in wild-type mice. CD39-/- mice had increased APAP-induced hemorrhage and mortality, whereas apyrase also decreased APAP-induced mortality. Kupffer cells were treated with extracellular ATP to assess P2X7-dependent inflammasome activation. P2X7 was required for ATP-stimulated IL-1 beta release. In conclusion, P2X7 and exposure to the ligands ATP and NAD are required for manifestations of APAP-induced hepatotoxicity.