Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation
Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation
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DOI：
10.1152/ajplung.00227.2010
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发表时间：
2011-05-01
影响因子：
4.9
通讯作者：
Lau, Christine L.
中科院分区：
文献类型：
--
作者：
Zhao, Yunge;Sharma, Ashish K.;Lau, Christine L.
赵勇，夏玛AK，LaPar DJ，Kron IL，Ailawadi G，刘毅，Jones Dr，Laubach VE，Lau CL。耗尽组织型纤溶酶原激活剂可通过抑制中性粒细胞外溢减轻肺缺血再灌注损伤。Am J Physiol肺细胞分子Physiol 300：L718-L729,2011。首次发表于2011年3月4日；肺移植后的胰岛素抵抗(doi:10.1152/ajplung.00227.2010.-Ischemia-reperfusion，IR)损伤仍然是早期发病率和死亡率的主要来源。组织学上，这种炎症过程的特点是中性粒细胞的渗透和激活。我们先前报道，纤溶酶原激活物抑制物-1缺陷小鼠的肺IR损伤显著减轻。在这项研究中，我们探讨了组织纤溶酶原激活物(TPA)在小鼠肺IR损伤模型中的潜在作用。结果，tPA基因敲除(KO)小鼠通过几种机制对肺IR损伤有显著的保护作用。在细胞水平上，tPA KO特异性地阻断了中性粒细胞向间质的外溢，并在肺微血管中检测到大量同型中性粒细胞聚集(HNA)。在分子水平上，抑制中性粒细胞外渗可能通过tPA/LDL受体相关蛋白/核因子-kappaB信号通路减少血小板内皮细胞黏附分子-1的表达，而增加P-选择素则可触发HNA。在功能水平上，tPA KO小鼠IR后血管通透性显著降低，肺功能明显改善。TPA KO小鼠对肺IR损伤的保护是通过不依赖纤溶的机制进行的。提示tPA可作为防治肺移植后急性IR损伤的重要治疗靶点。
Zhao Y, Sharma AK, LaPar DJ, Kron IL, Ailawadi G, Liu Y, Jones DR, Laubach VE, Lau CL. Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation. Am J Physiol Lung Cell Mol Physiol 300: L718-L729, 2011. First published March 4, 2011; doi:10.1152/ajplung.00227.2010.-Ischemia-reperfusion (IR) injury following lung transplantation remains a major source of early morbidity and mortality. Histologically, this inflammatory process is characterized by neutrophil infiltration and activation. We previously reported that lung IR injury was significantly attenuated in plasminogen activator inhibitor-1-deficient mice. In this study, we explored the potential role of tissue plasminogen activator (tPA) in a mouse lung IR injury model. As a result, tPA knockout (KO) mice were significantly protected from lung IR injury through several mechanisms. At the cellular level, tPA KO specifically blocked neutrophil extravasation into the interstitium, and abundant homotypic neutrophil aggregation (HNA) was detected in the lung microvasculature of tPA KO mice after IR. At the molecular level, inhibition of neutrophil extravasation was associated with reduced expression of platelet endothelial cell adhesion molecule-1 mediated through the tPA/ LDL receptor-related protein/NF-kappa B signaling pathway, whereas increased P-selectin triggered HNA. At the functional level, tPA KO mice incurred significantly decreased vascular permeability and improved lung function following IR. Protection from lung IR injury in tPA KO mice occurs through a fibrinolysis-independent mechanism. These results suggest that tPA could serve as an important therapeutic target for the prevention and treatment of acute IR injury after lung transplantation.