Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury
Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury
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DOI：
10.1172/jci94495
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发表时间：
2017-11-01
影响因子：
15.9
通讯作者：
Malik, Asrar B.
中科院分区：
文献类型：
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作者：
Cheng, Kwong Tai;Xiong, Shiqin;Malik, Asrar B.
急性肺损伤是细菌性脓毒症死亡的主要原因，因为肺内皮屏障遭到全面破坏，导致富含蛋白质的肺水肿、促炎性白细胞流入和顽固性低氧血症。细胞焦亡是一种由炎症性半胱天冬酶引发的程序性裂解细胞死亡形式，但人们对其在 EC 死亡和急性肺损伤中的作用知之甚少。在这里，我们发现全身暴露于细菌内毒素脂多糖（LPS）会导致严重的内皮细胞焦亡，这是由炎性半胱天冬酶、人EC中的人半胱天冬酶4/5或小鼠体内的鼠同源物半胱天冬酶11介导的。在 caspase-11 缺陷小鼠中，用 WT 造血细胞进行骨髓移植并不能消除内毒素血症引起的急性肺损伤，表明非造血 caspase-11 在内毒素血症中发挥核心作用。此外，EC 中 caspase-11 的条件性缺失可减少内毒素血症引起的肺水肿、中性粒细胞积聚和死亡。这些结果确立了内皮细胞焦亡在内毒素血症组织损伤中的必要作用，并表明内皮炎症半胱天冬酶是急性肺损伤的重要治疗靶点。
Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.