Cell-free hemoglobin-mediated human lung microvascular endothelial barrier dysfunction is not mediated by cell death.
Cell-free hemoglobin-mediated human lung microvascular endothelial barrier dysfunction is not mediated by cell death.
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DOI：
10.1016/j.bbrc.2021.03.161
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发表时间：
2021-06-04
影响因子：
3.1
通讯作者：
Meegan JE
中科院分区：
文献类型：
--
作者：
Tomasek T;Ware LB;Bastarache JA;Meegan JE
循环中的无细胞血红蛋白(CFH)在几种炎症和溶血条件下导致内皮损伤。我们和其他人已经证明CFH导致内皮通透性增加，但CFH介导的内皮屏障功能障碍的确切机制尚不完全清楚。基于我们之前在脓毒症小鼠模型中的研究表明，CFH增加了肺内的细胞凋亡，我们假设CFH通过这种细胞死亡机制导致内皮屏障功能障碍。我们首次证实CFH在体外导致人肺微血管屏障功能障碍，这可以被血红蛋白清除剂结合珠蛋白预防。虽然CFH引起了人肺微血管内皮细胞存活率的轻微但显著的下降，通过膜不透性的DNA染料Draq7测量，CFH并没有增加TUNEL染色或切割的caspase-3的蛋白质印迹测量的凋亡。此外，细胞凋亡抑制物(Z-VAD-FMK)、坏死抑制物(IM-54)、坏死抑制物(Necrostatin-1)、铁性下垂抑制物(Fe-statin-1)或自噬抑制物(3-甲基腺嘌呤)不能阻止CFH介导的内皮屏障功能障碍。我们的结论是，尽管CFH可能会随着时间的推移导致细胞活力的适度下降，但细胞死亡并不是CFH介导的肺微血管内皮屏障功能障碍的原因。
Circulating cell-free hemoglobin (CFH) contributes to endothelial injury in several inflammatory and hemolytic conditions. We and others have shown that CFH causes increased endothelial permeability, but the precise mechanisms of CFH-mediated endothelial barrier dysfunction are not fully understood. Based on our previous study in a mouse model of sepsis demonstrating that CFH increased apoptosis in the lung, we hypothesized that CFH causes endothelial barrier dysfunction through this cell death mechanism. We first confirmed that CFH causes human lung microvascular barrier dysfunction in vitro that can be prevented by the hemoglobin scavenger, haptoglobin. While CFH caused a small but significant decrease in cell viability measured by the membrane impermeable DNA dye Draq7 in human lung microvascular endothelial cells, CFH did not increase apoptosis as measured by TUNEL staining or western blot for cleaved caspase-3. Moreover, inhibitors of apoptosis (Z-VAD-FMK), necrosis (IM-54), necroptosis (necrostatin-1), ferroptosis (ferrostatin-1), or autophagy (3-methyladenine) did not prevent CFH-mediated endothelial barrier dysfunction. We conclude that although CFH may cause a modest decrease in cell viability over time, cell death does not contribute to CFH-mediated lung microvascular endothelial barrier dysfunction.
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影响因子：
8.8
作者：
Miyake, K;McNeil, PL
通讯作者：
McNeil, PL
DOI：
10.1165/rcmb.2017-0308oc
发表时间：
2018-09-01
影响因子：
6.4
作者：
Rafikova, Olga;Williams, Elissa R.;Rafikov, Ruslan
通讯作者：
Rafikov, Ruslan
DOI：
10.1186/cc11425
发表时间：
2012-07-16
期刊：
Critical care (London, England)
影响因子：
--
作者：
Adamzik M;Hamburger T;Petrat F;Peters J;de Groot H;Hartmann M
通讯作者：
Hartmann M
影响因子：
5.3
作者：
Andrews AM;Lutton EM;Merkel SF;Razmpour R;Ramirez SH
通讯作者：
Ramirez SH
影响因子：
4
作者：
Jana S;Meng F;Hirsch RE;Friedman JM;Alayash AI
通讯作者：
Alayash AI