Extracellular Adenosine Production by Ecto-5′-Nucleotidase Protects During Murine Hepatic Ischemic Preconditioning
Extracellular Adenosine Production by Ecto-5′-Nucleotidase Protects During Murine Hepatic Ischemic Preconditioning
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DOI：
10.1053/j.gastro.2008.07.064
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发表时间：
2008-11-01
期刊：
影响因子：
29.4
通讯作者：
Eltzschig, Holger K.
中科院分区：
文献类型：
--
作者：
Hart, Melanie L.;Much, Chressen;Eltzschig, Holger K.
背景与目的：肝脏对缺血再灌注（IR）的耐受性较差。缺血预处理（IP）的发现为激活自然通路以增强肝脏对缺血的抵抗带来了希望。然而，肝脏IP的机制在很大程度上仍然未知。细胞外腺苷被认为是一种天然的抗炎代谢物，特别是在缺血时。我们研究了胞外腺苷生成的“起搏器”酶外s核苷酸酶（CD73）是否对IP对肝脏的保护至关重要。方法：小鼠在IR或单独IR前进行4个周期的门静脉三合一闭塞再灌注（缺血3分钟/再灌注3分钟）。结果：肝脏IP与CD73转录物和蛋白的显著诱导相关。通过乳酸脱氢酶、天冬氨酸转氨酶和丙氨酸转氨酶的血清水平或组织损伤来测定，靶向基因缺失或药物抑制CD73可破坏IP对肝脏的保护作用。在cd73缺陷（cd73(-/-)）小鼠中，细胞外腺苷的增加与IP显著减弱。用可溶性5′-核苷酸酶重建cd73（-/-）小鼠可完全恢复IP对肝脏的保护作用，用可溶性5′-核苷酸酶治疗WT小鼠可减轻缺血后的肝损伤。缺乏CD73的小鼠没有表现出与野生型小鼠相同程度的急性期补体基因表达/激活的ip依赖性抑制，这表明细胞外腺苷通过补体调节减弱了肝脏IR。结论：CD73细胞外腺苷产生介导小鼠肝脏IP保护。使用可溶性5′-核苷酸酶可能是治疗肝缺血的一种潜在方法。
Background & Aims: The liver tolerates ischemia/reperfusion (IR) poorly. The discovery of ischemic preconditioning (IP) has raised hopes that natural pathways could be activated to increase hepatic resistance to ischemia. However, mechanisms of hepatic IP remain largely unknown. Extracellular adenosine has been implicated as an innate anti-inflammatory metabolite, particularly during ischemia. We investigated whether ecto-S'-nucleotidase (CD73), the "pacemaker" enzyme of extracellular adenosine production, is critical for hepatic protection by IP. Methods: Mice were subjected to 4 cycles of portal triad occlusion and reperfusion (3 minutes of ischemia/3 minutes of reperfusion) prior to IR or IR alone. Results: Hepatic IP was associated with a significant induction of CD73 transcript and protein. Targeted gene deletion or pharmacologic inhibition of CD73 abolished hepatic protection by IP as measured by lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase serum levels or histologic injury. Increases in extracellular adenosine with IP were significantly attenuated in cd73-deficient (cd73(-/-)) mice. Reconstitution of cd73(-/-) mice with soluble 5'-nucleotidase resulted in complete restoration of hepatoprotection by IP, and hepatic injury following ischemia was attenuated by treatment of WT mice with soluble 5'-nucleotidase. Mice deficient in CD73 did not demonstrate the same degree of IP-dependent inhibition of acute phase complement gene expression/activation as did wild-type mice suggesting that extracellular adenosine attenuates hepatic IR via complement regulation. Conclusions: Extracellular adenosine production by CD73 mediates protection during murine hepatic IP. Use of soluble 5'-nucleotidase may be a potential therapeutic for hepatic ischemia.