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.

中文翻译：

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Caspase-11介导的内皮细胞凋亡是内毒素血症引起的肺损伤的基础

急性肺损伤是由于肺内皮屏障的全面破坏而导致细菌性败血症死亡的主要原因，这会导致富含蛋白质的肺水肿，促炎性白细胞大量涌入以及顽固性低氧血症。细胞凋亡是炎症性胱天蛋白酶触发的程序性裂解细胞死亡的一种形式，但对其在EC死亡和急性肺损伤中的作用知之甚少。在这里，我们显示全身暴露于细菌内毒素脂多糖（LPS）会导致严重的内皮细胞凋亡，这是由炎症性胱天蛋白酶，人EC中4/5的人胱天蛋白酶或小鼠体内的鼠同源半胱天冬酶11介导的。在缺乏caspase-11的小鼠中，用WT造血细胞进行BM移植不能消除内毒素血症引起的急性肺损伤，提示非造血性caspase-11在内毒素血症中具有重要作用。此外，在EC中有条件地删除caspase-11可以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凋亡在内毒素性组织损伤中的必要作用，并表明内皮炎性胱天蛋白酶是急性肺损伤的重要治疗靶标。