Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism
Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism
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DOI：
10.1182/blood-2004-06-2066
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发表时间：
2004-12-15
期刊：
影响因子：
20.3
通讯作者：
Colgan, SP
中科院分区：
文献类型：
--
作者：
Eltzschig, HK;Thompson, LF;Colgan, SP
缺氧是一种有据可查的炎症刺激，可导致组织多形核白细胞（PMN）蓄积。同样地，组织腺苷水平的增加通常与缺氧相关，并且鉴于腺苷的抗炎特性，我们假设在缺氧期间通过血管表面的腺嘌呤核苷酸代谢产生的腺苷触发内源性抗炎反应。初步的体外研究表明，内源性产生的腺苷，通过激活PMN腺苷A（2A）和A（2B）受体，作为PMN结合微血管内皮细胞的抗粘附信号。炎症细胞释放的血管内核苷酸通过缺氧诱导的CD 39外腺苷三磷酸双磷酸酶（CD 39将三磷酸腺苷/二磷酸腺苷[ATP/ADP]转化为单磷酸腺苷[AMP]）和CD 73外-5 '-核苷酸酶（CD 73将AMP转化为腺苷）进行磷酸水解。我们在体外研究结果的扩展，使用cd 39和cd 73空的动物显示，细胞外腺苷产生的腺嘌呤核苷酸代谢过程中缺氧是一个有效的抗炎信号的中性粒细胞在体内。这些发现确定了CD 39和CD 73作为内源性腺苷生成的关键控制点，并暗示该途径是减弱组织PMN过度积聚的先天机制。(C)2004年，美国血液学会。
Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of adenosine, we hypothesized that adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated adenosine, through activation of PMN adenosine A(2A) and A(2B) receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts adenosine triphosphate/adenosine diphosphate [ATP/ADP] to adenosine monophosphate [AMP]) and CD73 ecto-5'-nucleotidase (CD73 converts AMP to adenosine). Extensions of our in vitro findings using cd39-and cd73-null animals revealed that extra-cellular adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation. (C) 2004 by The American Society of Hematology.