Human Neutrophil Defensins Disrupt Liver Interendothelial Junctions and Aggravate Sepsis.
Human Neutrophil Defensins Disrupt Liver Interendothelial Junctions and Aggravate Sepsis.
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DOI：
10.1155/2022/7659282
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发表时间：
2022
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
人中性粒细胞肽 1-3 (HNP1-3)，也称为人 α-防御素，是最丰富的中性粒细胞颗粒蛋白。编码 HNP1-3、DEFA1/DEFA3 的基因表现出广泛的拷贝数变异，这与其蛋白质水平密切相关。人类和小鼠研究表明，DEFA1/DEFA3 拷贝数增加会加重脓毒症结局。此外，据报道脓毒症患者体液中 HNP1-3 浓度较高。然而，缺乏 HNP1-3 蛋白在脓毒症进展过程中致病作用的直接证据。目前的研究中，通过盲肠穿刺和结扎诱发脓毒症。脓毒症发作后6小时，给小鼠腹腔注射不同剂量的HNP-1（低剂量0.5mg/kg体重和高剂量10mg/kg体重）或磷酸盐缓冲盐水。监测存活率，并评估血管通透性、内皮细胞焦亡和内皮粘附连接蛋白血管内皮钙粘蛋白的免疫荧光。脓毒症发作后给予高剂量的 HNP-1 会导致死亡率增加、肝损伤更严重以及肝脏和肠系膜血管通透性增加。注射高剂量的HNP-1并不直接诱导肝内皮细胞死亡，而是破坏了肝脏内的内皮细胞连接。此外，核苷酸结合寡聚结构域样受体蛋白3或caspase-1的遗传缺陷消除了脓毒症期间高剂量HNP-1引起的高死亡率和肝内皮连接破坏。这项研究直接证明了中性粒细胞防御素在脓毒症发展过程中调节内皮稳定性方面发挥着关键作用。
Human neutrophil peptides 1-3 (HNP1-3), also known as human α-defensins, are the most abundant neutrophil granule proteins. The genes that encode HNP1-3, DEFA1/DEFA3, exhibit extensive copy number variations, which correlate well with their protein levels. Human and mouse studies have shown that increased copy numbers of DEFA1/DEFA3 worsen sepsis outcomes. Additionally, high concentrations of HNP1-3 in body fluids have been reported in patients with sepsis. However, direct evidence for the pathogenic role of HNP1-3 proteins during sepsis progression is lacking. In current study, sepsis was induced by means of cecal puncture and ligation. Various doses of HNP-1 (low dose with 0.5 mg/kg body weight and high dose with 10 mg/kg body weight) or phosphate buffer saline were intraperitoneally administered to mice at six hours after sepsis onset. Survival rate was monitored, and vascular permeability, endothelial cell pyroptosis, and immunofluorescence of endothelial adherens junction protein vascular endothelial-cadherin were evaluated. The administration of a high dose of HNP-1 after sepsis onset led to increased mortality, more severe liver injury, and increased vascular permeability in the liver and mesentery. The injection of high dose of HNP-1 did not directly induce liver endothelial cell death but destroyed interendothelial junctions in the liver. Moreover, genetic deficiency of nucleotide-binding oligomerization domain-like receptor protein-3 or caspase-1 abrogated the high mortality and disrupted liver interendothelial junctions caused by high dose of HNP-1 during sepsis. This study directly demonstrates that neutrophil defensins play a key role in regulating endothelial stability during sepsis development.
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影响因子：
17.1
作者：
London NR;Zhu W;Bozza FA;Smith MC;Greif DM;Sorensen LK;Chen L;Kaminoh Y;Chan AC;Passi SF;Day CW;Barnard DL;Zimmerman GA;Krasnow MA;Li DY
通讯作者：
Li DY
影响因子：
5.3
作者：
Chen Y;Pitzer AL;Li X;Li PL;Wang L;Zhang Y
通讯作者：
Zhang Y
影响因子：
7.3
作者：
Martin L;van Meegern A;Doemming S;Schuerholz T
通讯作者：
Schuerholz T
影响因子：
6.7
作者：
Soong, LB;Ganz, T;Caughey, GH
通讯作者：
Caughey, GH
影响因子：
11.8
作者：
Ihi, T;Nakazato, M;Matsukura, S
通讯作者：
Matsukura, S