NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury
NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury
复制标题
肺血管内皮细胞中 NLRP3 炎症小体的激活导致肠缺血/再灌注引起的急性肺损伤
DOI：
10.4049/jimmunol.2000217
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发表时间：
2020-09-01
影响因子：
4.4
通讯作者：
Takahashi, Masafumi
中科院分区：
文献类型：
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作者：
Ito, Homare;Kimura, Hiroaki;Takahashi, Masafumi
肠缺血/再灌注(I/R)损伤是一种危及生命的并发症，可导致炎症和远隔器官损伤。NLRP3炎症体调节依赖caspase-1的IL-1β的释放，IL-1β是I/R损伤后炎症的早期介质。在本研究中，我们研究了NLRP3炎症体在小鼠肠I/R损伤中的作用。NLRP3、ASC、caspase-1/11或IL-1β缺乏可延长肠I/R损伤后的存活时间，但NLRP3和caspase-1/11缺乏均不影响肠炎症。肠I/R损伤可导致急性肺损伤(ALI)，表现为炎症反应、活性氧生成和血管通透性，NLRP3缺乏可显著改善ALI。骨髓嵌合实验表明，非骨髓源性细胞中的NLRP3是肠I/R所致ALI发生的主要原因。肺血管内皮细胞中的NLRP3炎性小体被认为对肺血管通透性具有重要作用。使用质谱仪，我们鉴定了肠I/R衍生的脂质介质，它促进了肺血管内皮细胞中NLRP3炎症体的激活。最后，我们证实了肠缺血患者血清中这些脂质介质的水平升高。据我们所知，这些发现为肠道I/R诱导ALI的机制提供了新的见解，并表明内皮NLRP3炎症驱动的IL-1β是治疗和预防这种疾病的新的潜在靶点。
Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1 beta, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1 beta prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1 beta is a novel potential target for treating and preventing this disorder.