内皮细胞敲除TFPI对小鼠急性肺损伤的影响

Effect of Endothelial Cell-anchored Tissue Factor Pathway Inhibitor on Acute Lung Injury in Mice

目的本研究旨在阐明内皮细胞特异性敲除TFPI对内毒素引起小鼠急性肺损伤的影响和可能机制。方法采用气管内滴注内毒素建立急性肺损伤小鼠模型。与野生型小鼠比较,评价内皮细胞中的TFPI对急性肺损伤内皮细胞屏障功能和炎性反应的作用,评价内皮细胞敲除TFPI后对炎性信号通路NF-κB通路的影响。结果内皮细胞敲除TFPI可以明显加重内毒素所引起急性肺损伤的肺部病理改变,增加肺泡灌洗液中蛋白含量及伊文思蓝的渗透,促进肺组织及肺泡灌洗液中炎性因子TNF-α、IL-1β和IL-6的分泌。内皮细胞敲除TFPI小鼠与野生型内毒素诱导的急性肺损伤小鼠比较,肺泡灌洗液及肺组织中炎性细胞浸润增加。研究发现内皮细胞TFPI敲除与野生型小鼠相比内毒素诱导后,其炎性信号通路NF-κB激活更加明显。以上研究结果证实内皮细胞TFPI敲除小鼠急性肺损伤后肺组织中的炎性反应和血管渗透性都明显增加。结论特异性内皮细胞TFPI敲除小鼠,在内毒素诱导的急性肺损伤模型中,通过对NF-κB信号通路的激活来促进肺组织的炎性反应和血管内皮细胞的通透性。

Objective To investigate the effect and mechanism of endothelial cell-anchored TFPI on LPS-induced acute lung injury in mice.Methods To assess the effect of endothelial cell-anchored TFPI deletion on ALI,the TFPI cKO mice were generated.Mice were instilled by direct intratracheal injection lipopolysaccharides for the preparation of acute lung injury mice model.To assess the effect of TFPI on endothelial barrier function and inflammation,activation of NF-κB pathway and some relative indicators were measured between TFPI fl/fl/Tek mice and WT mice.Results The deletion of endothelial TFPI markedly exacerbated LPS-induced histopathologic changes of lung,protein and EB extravasation into BALF,and promoted the secretion of proinflammatory cytokines TNF-α,IL-1βand IL-6.The infiltration of white Blood Cells(WBC)from BALF and lung tissue of TFPI cKO mice with LPS-challenged ALI had increased compared to WT mice with LPS-challenged ALI.We found that further increased NF-κB activation in TFPI cKO mice than WT mice upon LPS administration.These results are consistent with the results that LPS-induced lung injury could enhance inflammatory and vascular permeability responses in TFPI cKO mice.Conclusion The deficiency of endothelial specific TFPI not only promoted pulmonary inflammation and endothelial barrier permeability but also caused NF-κB signaling pathway activation in LPS-induced acute lung injury mouse model.