Knockdown of TFPI-Anchored Endothelial Cells Exacerbates Lipopolysaccharide-Induced Acute Lung Injury Via NF-κB Signaling Pathway.
Knockdown of TFPI-Anchored Endothelial Cells Exacerbates Lipopolysaccharide-Induced Acute Lung Injury Via NF-κB Signaling Pathway.
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TFPI 锚定内皮细胞的敲低通过 NF-κB 信号通路加剧脂多糖诱导的急性肺损伤
DOI：
10.1097/shk.0000000000001120
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Bai CX
中科院分区：
文献类型：
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作者：
Wang BQ;Shi M;Zhang JP;Wu X;Chang MJ;Chen ZH;Shen HH;Song YL;Zhou J;Bai CX
由于凝血系统的激活既是急性肺损伤（ALI）的结果，也是其促成因素，因此肺凝血病已成为ALI患者治疗干预的潜在靶点。本研究探讨了内皮细胞锚定的组织因子途径抑制剂（TFPI）对脂多糖（LPS）诱导的小鼠急性肺损伤（ALI）的影响及其可能机制。为了评估EC锚定的TFPI缺失对ALI指数的影响，产生TFPI敲除（cKO）小鼠。通过直接气管内注射LPS制备小鼠ALI模型。在动物处死前2小时（LPS后48小时）静脉内注射伊文思蓝染料（EBD）。 将肺固定用于组织病理学检查，并将制备的组织匀浆或用于提取支气管肺泡灌洗液（BALF）或检测EBD浓度。将患有ALI的TFPI敲低小鼠与患有ALI的野生型（WT）小鼠进行比较，以评估TFPI对内皮屏障功能和炎症的影响。TFPI基因缺失可明显加重肺组织病理学改变，加重肺内LPS蛋白、EBD外渗及BALF中TNF-α、IL-1β、IL-6的变化。与患有LPS-激发的ALI的WT小鼠相比，患有LPS-激发的ALI的TFPI cKO小鼠的BALF和肺组织中的白色血细胞（WBC）的数量和浸润增加。我们还发现与WT+LPS小鼠相比，TFPI cKO+LPS小鼠中活化的B细胞活化的Toll样受体4和核因子κ轻链增强子进一步增加，血管细胞粘附分子1的额外表达和血管紧张素转换酶2表达的减少。内皮特异性TFPI缺乏可能通过Toll样受体4介导的活化B细胞核因子κ轻链增强子信号通路激活促进LPS诱导的肺部炎症和内皮屏障通透性。
As activation of the coagulation system is both a consequence and contributor to acute lung injury (ALI), pulmonary coagulopathy has become a potential target for therapeutic intervention in ALI patients. We investigated the effects and possible mechanisms of endothelial cell (EC)-anchored tissue factor pathway inhibitor (TFPI) on lipopolysaccharide (LPS)-induced ALI in mice. To assess the effect of EC-anchored TFPI deletion on ALI indices, TFPI knockout (cKO) mice were generated. Mice were instilled by direct intratracheal injection LPS for the preparation of an ALI model. Evans blue dye (EBD) was injected intravenously 2 h prior to animal sacrifice (48 h post-LPS). Lungs were fixed for histopathology and the prepared tissue was homogenized or used to extract bronchoalveolar lavage fluid (BALF) or detect EBD concentration. TFPI knockdown mice with ALI were compared to wild-type (WT) mice with ALI to assess the effect of TFPI on endothelial barrier function and inflammation. TFPI deletion markedly exacerbated LPS histopathological changes in lung, and the LPS changes in protein, EBD extravasation, proinflammatory cytokines TNF-α, IL-1β, and IL-6 in BALF in lung. The number and infiltration of white blood cells (WBCs) from BALF and lung tissue of TFPI cKO mice with LPS-challenged ALI was increased compared to WT mice with LPS-challenged ALI. We also found further increased toll-like receptor 4 and nuclear factor kappa-light-chain-enhancer of activated B cells activation and additional expression of vascular cell adhesion molecule 1 and reduction of angiotensin converting enzyme 2 expression in TFPI cKO+LPS mice compared with WT+LPS mice. Endothelial-specific TFPI deficiency promoted LPS-induced pulmonary inflammation and endothelial barrier permeability possibly via toll-like receptor 4-mediated nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway activation.