Neutrophil-Endothelial Interactions Mediate Angiopoietin-2-Associated Pulmonary Endothelial Cell Dysfunction in Indirect Acute Lung Injury in Mice
Neutrophil-Endothelial Interactions Mediate Angiopoietin-2-Associated Pulmonary Endothelial Cell Dysfunction in Indirect Acute Lung Injury in Mice
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DOI：
10.1165/rcmb.2013-0148oc
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发表时间：
2014-01-01
影响因子：
6.4
通讯作者：
Ayala, Alfred
中科院分区：
文献类型：
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作者：
Lomas-Neira, Joanne;Venet, Fabienne;Ayala, Alfred
肺部未解决的炎症被认为会导致内皮细胞（EC）屏障完整性丧失和肺功能受损。我们在休克/脓毒症小鼠模型中证明，中性粒细胞与常驻肺细胞的相互作用似乎是间接急性肺损伤（iALI）发病机制的核心。正常情况下，EC 生长因子血管生成素 (Ang)-1 和 Ang-2 通过与 EC 上表达的激酶受体 Tie2 的严格调节相互作用来维持血管稳态。尽管 Ang-1/Tie2 已被证明可以促进血管完整性，刺激下游促生存/抗炎信号传导，但据报道，从激活的 EC 中释放的 Ang-2 会促进血管不稳定。这种调节机制，加上最近的临床发现（急性呼吸窘迫综合征患者血浆 Ang-2 水平显着升高），使我们的研究重点放在 Ang-2 对 iALI 发展的贡献上。本研究使用了失血性休克引发的小鼠模型，该模型在随后的脓毒症攻击后引发 iALI 的发展。我们的研究结果表明，1) Ang-2 在我们的 iALI 实验模型中升高，2) EC/中性粒细胞直接相互作用显着促进 ECAng-2 释放，3) 抑制 Ang-2 显着减少炎症性肺损伤、中性粒细胞流入以及肺和血浆 IL-6 和 TNF-α。这些发现支持我们的假设，并表明 Ang-2 在小鼠因失血性休克和脓毒症的连续损伤而发生 iALI 的过程中，在肺 EC 屏障功能丧失中发挥作用，并且这是由 EC 与活化的中性粒细胞相互作用介导的。
Unresolved inflammation in the lung is thought to elicit loss of endothelial cell (EC) barrier integrity and impaired lung function. We have shown, in a mouse model of shock/sepsis, that neutrophil interactions with resident pulmonary cells appear central to the pathogenesis of indirect acute lung injury (iALI). Normally, EC growth factors angiopoietin (Ang)-1 and Ang-2 maintain vascular homeostasis through tightly regulated interaction with the kinase receptor Tie2 expressed on ECs. Although Ang-1/Tie2 has been shown to promote vessel integrity, stimulating downstream prosurvival/antiinflammatory signaling, Ang-2, released from activated ECs, is reported to promote vessel destabilization. This mechanism of regulation, together with recent clinical findings that plasma Ang-2 levels are significantly elevated in patients who develop acute respiratory distress syndrome, has focused our investigation on the contribution of Ang-2 to the development of iALI. A murine model of hemorrhagic shock-induced priming for the development of iALI after subsequent septic challenge was used in this study. Our findings show that 1) Ang-2 is elevated in our experimental model for iALI, 2) direct EC/neutrophil interactions contribute significantly to ECAng-2 release, and 3) suppression of Ang-2 significantly decreases inflammatory lung injury, neutrophil influx, and lung and plasma IL-6 and TNF-alpha. These findings support our hypothesis and suggest that Ang-2 plays a role in the loss of pulmonary EC barrier function in the development of iALI in mice resultant from the sequential insults of hemorrhagic shock and sepsis and that this is mediated by EC interaction with activated neutrophils.