The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.
The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.
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DOI：
10.1038/nm.2843
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发表时间：
2012-08
期刊：
影响因子：
82.9
通讯作者：
Tuder, Rubin M.
中科院分区：
文献类型：
--
作者：
Schmidt, Eric P.;Yang, Yimu;Janssen, William J.;Gandjeva, Aneta;Perez, Mario J.;Barthel, Lea;Zemans, Rachel L.;Bowman, Joel C.;Koyanagi, Dan E.;Yunt, Zulma X.;Smith, Lynelle P.;Cheng, Sara S.;Overdier, Katherine H.;Thompson, Kathy R.;Geraci, Mark W.;Douglas, Ivor S.;Pearse, David B.;Tuder, Rubin M.
脓毒症是对感染的全身性炎症反应，通常进展为急性肺损伤（ALI），这是一种发病率较高的炎性肺病。我们推测脓毒症相关的急性肺损伤是由肺内皮细胞糖萼的降解引起的，导致中性粒细胞粘附和炎症。利用活体显微镜，我们发现小鼠内毒素血症通过肿瘤坏死因子-α（TNF-α）依赖性机制快速诱导肺微血管糖萼降解。糖萼降解涉及硫酸乙酰肝素的特异性损失，并与内皮乙酰肝素酶（一种TNF-α响应性硫酸乙酰肝素特异性葡萄糖醛酸酶）的活化一致。糖萼降解增加了内皮细胞表面粘附分子对循环微球的可用性，并有助于中性粒细胞粘附。乙酰肝素酶抑制剂可防止内毒素血症相关的糖萼丢失和中性粒细胞粘附，从而减轻脓毒症诱导的小鼠ALI和死亡率。这些发现可能与人类疾病相关，因为人类败血症相关呼吸衰竭与较高的血浆硫酸乙酰肝素降解活性相关;此外，显示弥漫性肺泡损伤的人肺活检组织中乙酰肝素酶含量高于正常人肺组织。
Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α–responsive, heparan sulfate–specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.
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