AMP deaminase 3 plays a critical role in remote reperfusion lung injury
AMP deaminase 3 plays a critical role in remote reperfusion lung injury
复制标题
DOI：
10.1016/j.bbrc.2013.03.056
复制
发表时间：
2013-04-26
影响因子：
3.1
通讯作者：
Hisatome, Ichiro
中科院分区：
文献类型：
--
作者：
Li, Peili;Ogino, Kazuhide;Hisatome, Ichiro
骨骼肌缺血再灌注后的远隔再灌注肺损伤具有较高的发病率和死亡率。腺苷酸脱氨酶（AMP deaminase，AMPD）是核苷酸循环的关键酶，参与了这一过程的调控。然而，Ampd 2和Ampd 3亚型在远程再灌注大鼠肺损伤中的功能尚未阐明。我们使用AMPD 3和AMPD 2缺陷型小鼠。对两种类型的AMPD缺陷型小鼠和野生型（WT）同窝小鼠进行缺血再灌注损伤。双后肢缺血再灌注3 h后，WT和AMPD 2基因敲除小鼠肺组织中AMPD 3 mRNA、AMPD活性和IMP均显著升高，而AMPD 3基因敲除小鼠肺组织中AMPD 3 mRNA、AMPD活性和IMP均无明显变化。与WT和AMPD 2缺陷小鼠相比，Ampd 3基因失活导致肺中髓过氧化物酶（MPO）活性沿着过度的中性粒细胞浸润和出血，此外，IMP处理显著减弱了再灌注3 h后WT和两种类型的AMPD缺陷小鼠肺中MPO活性和中性粒细胞浸润。这些发现首次在AMP缺陷小鼠模型中证明，AMPD 3通过产生IMP在远程再灌注肺损伤中起关键作用，并验证了将IMP用于临床竞技场以减轻远程缺血-再灌注肺损伤的潜力。(C)2013 Elsevier Inc. All rights reserved.
Remote reperfusion lung injury following skeletal muscle ischemia and reperfusion accounts for high morbidity and mortality. AMP deaminase (AMPD), a key enzyme for nucleotide cycle, has been implicated in the regulation of this phenomenon. However, the function of Ampd2 and Ampd3 subtype has not been elucidated in remote reperfusion rodent lung injury. We utilized AMPD3 and AMPD2-deficient mice. The two types of AMPD-deficient mice and wild-type (WT) littermates were subjected to ischemia-reperfusion injury. After 3 h bilateral hind-limb ischemia and reperfusion, AMPD3 mRNA, AMPD activity and inosine monophosphate (IMP) increased significantly in WT and AMPD2-deficient mice lungs, while they did not show significant alterations in AMPD3-deficient mice lungs. Genetic inactivation of Ampd3 resulted in markedly accelerated myeloperoxidase (MPO) activity along with exaggerated neutrophils infiltration and hemorrhage in the lungs compared to WT and AMPD2-deficient mice, furthermore, IMP treatment significantly attenuated MPO activity and neutrophils infiltration in WT and the two types of AMPD-deficient mice lungs after 3 h reperfusion. These findings demonstrate for the first time in AMP-deficient mice models that AMPD3 plays a critical role in remote reperfusion lung injury via generation of IMP and validate the potential to use IMP into the clinical arena to attenuate remote ischemia-reperfusion lung injury. (C) 2013 Elsevier Inc. All rights reserved.