EXOCYTOSIS OF ENDOTHELIAL LYSOSOME‐RELATED ORGANELLES HAIR‐TRIGGERS A PATCHY LOSS OF GLYCOCALYX AT THE ONSET OF SEPSIS
EXOCYTOSIS OF ENDOTHELIAL LYSOSOME‐RELATED ORGANELLES HAIR‐TRIGGERS A PATCHY LOSS OF GLYCOCALYX AT THE ONSET OF SEPSIS
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DOI：
10.1016/j.ajpath.2015.10.001
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
J. Zullo;Jie Fan;Tala Azar;Wanyi Yen;Min Zeng;Jun Chen;Brian B. Ratliff;Jun Song;J. Tarbell;M. Goligorsky;B. Fu
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文献类型：
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作者：
J. Zullo;Jie Fan;Tala Azar;Wanyi Yen;Min Zeng;Jun Chen;Brian B. Ratliff;Jun Song;J. Tarbell;M. Goligorsky;B. Fu
脓毒症是一种由细菌感染引起的系统性炎症综合征，可导致多器官衰竭。内皮表面糖萼（Endothelial surface glycocalyx， ESG）位于血管内壁，是多种血管功能的调节剂。在这里，我们验证了一个假设，即ESG的斑片状降解发生在败血症的早期，是溶酶体相关细胞器胞吐的结果。延时视频显微镜显示，在脂多糖作用于内皮细胞几分钟后，维贝尔-帕拉体和分泌溶酶体发生胞吐。两种治疗方法，一氧化氮中间体，ng -羟基-l-精氨酸和内皮祖细胞调节的培养基降低了溶酶体相关细胞器的运动性。共聚焦和随机光学重建显微镜证实，在培养的内皮细胞和小鼠主动脉中，溶酶体相关细胞器和webel - palade小体胞外分泌的同时，ESG呈斑块状丢失。用ng -羟基-l-精氨酸预处理或内皮祖细胞调节的培养基可以减弱ESG的损失。此外，这些治疗还显著降低了脓毒症小鼠的死亡率。我们的数据支持这样的假设，即应激诱导的细胞器胞外分泌对ESG的局部降解起着一触即发的作用，从而引发白细胞浸润，增加血管通透性，并部分解释了后来的发病率和死亡率。
Sepsis is a systemic inflammatory syndrome induced by bacterial infection that can lead to multiorgan failure. Endothelial surface glycocalyx (ESG) decorating the inner wall of blood vessels is a regulator of multiple vascular functions. Here, we tested a hypothesis that patchy degradation of ESG occurs early in sepsis and is a result of exocytosis of lysosome-related organelles. Time-lapse video microscopy revealed that exocytosis of Weibel-Palade bodies and secretory lysosomes occurred a few minutes after application of lipopolysaccharides to endothelial cells. Two therapeutic maneuvers, a nitric oxide intermediate, NG-hydroxy-l-arginine, and culture media conditioned by endothelial progenitor cells reduced the motility of lysosome-related organelles. Confocal and stochastic optical reconstruction microscopy confirmed the patchy loss of ESG simultaneously with the exocytosis of lysosome-related organelles and Weibel-Palade bodies in cultured endothelial cells and mouse aorta. The loss of ESG was blunted by pretreatment with NG-hydroxy-l-arginine or culture media conditioned by endothelial progenitor cells. Moreover, these treatments resulted in a significant reduction in deaths of septic mice. Our data support the hypothesis assigning to stress-induced exocytosis of these organelles the role of a hair-trigger for local degradation of ESG that initiates leukocyte infiltration, increase in vascular permeability, and partially accounts for the later rates of morbidity and mortality.