Rabeprazole Promotes Vascular Repair and Resolution of Sepsis-Induced Inflammatory Lung Injury through HIF-1α.
Rabeprazole Promotes Vascular Repair and Resolution of Sepsis-Induced Inflammatory Lung Injury through HIF-1α.
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雷帕霉素通过HIF-1α促进血管修复和脓毒症诱导的炎性肺损伤的消退
DOI：
10.3390/cells11091425
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发表时间：
2022-04-22
期刊：
影响因子：
6
通讯作者：
Zhao, You-Yang
中科院分区：
文献类型：
--
作者：
Evans, Colin E.;Peng, Yi;Zhu, Maggie M.;Dai, Zhiyu;Zhang, Xianming;Zhao, You-Yang
目前尚无有效的治疗败血症和急性呼吸窘迫综合征（ARDS）的方法。重新定位现有药物可能是治疗败血症和ARDS的有效策略之一。我们之前的研究表明，血管修复和脓毒症诱导的炎症性肺损伤的解决依赖于内皮HIF-1α/FoxM1信号。本研究的目的是确定HIF-1α/FoxM1信号的候选诱导剂，用于治疗败血症和ARDS。通过使用缺氧反应元件（HRE）驱动的荧光素酶报告基因检测对1200种fda批准的药物库进行高通量筛选，我们确定了雷贝拉唑（也称为Aciphex）是一种顶级的HIF-α激活剂。在培养的人肺微血管内皮细胞中，雷贝拉唑诱导HIF1A mRNA表达呈剂量依赖性。在内毒素诱导的炎症性肺损伤小鼠模型中，雷贝拉唑的剂量反应研究确定了一个耐受性良好的剂量，并增强了血管修复和炎症性肺损伤的消退。雷贝拉唑治疗导致修复期肺血管渗漏、水肿、中性粒细胞隔离和促炎细胞因子表达减少。接下来，我们使用Hif1a/Tie2Cre敲除小鼠和Foxm1/Tie2Cre敲除小鼠来证明雷贝拉唑通过HIF-1α/ Foxm1信号传导促进血管修复。综上所述，雷别拉唑是一种有效的HIF-1α诱导剂，通过内皮HIF-1α/FoxM1信号通路促进血管修复和脓毒症诱导的炎症性肺损伤的消退。因此，这种药物代表了一种有希望的候选药物，可用于有效治疗严重败血症和ARDS。
There are currently no effective treatments for sepsis and acute respiratory distress syndrome (ARDS). The repositioning of existing drugs is one possible effective strategy for the treatment of sepsis and ARDS. We previously showed that vascular repair and the resolution of sepsis-induced inflammatory lung injury is dependent upon endothelial HIF-1α/FoxM1 signaling. The aim of this study was to identify a candidate inducer of HIF-1α/FoxM1 signaling for the treatment of sepsis and ARDS. Employing high throughput screening of a library of 1200 FDA-approved drugs by using hypoxia response element (HRE)-driven luciferase reporter assays, we identified Rabeprazole (also known as Aciphex) as a top HIF-α activator. In cultured human lung microvascular endothelial cells, Rabeprazole induced HIF1A mRNA expression in a dose-dependent manner. A dose-response study of Rabeprazole in a mouse model of endotoxemia-induced inflammatory lung injury identified a dose that was well tolerated and enhanced vascular repair and the resolution of inflammatory lung injury. Rabeprazole treatment resulted in reductions in lung vascular leakage, edema, and neutrophil sequestration and proinflammatory cytokine expression during the repair phrase. We next used Hif1a/Tie2Cre knockout mice and Foxm1/Tie2Cre knockout mice to show that Rabeprazole promoted vascular repair through HIF-1α/FoxM1 signaling. In conclusion, Rabeprazole is a potent inducer of HIF-1α that promotes vascular repair and the resolution of sepsis-induced inflammatory lung injury via endothelial HIF-1α/FoxM1 signaling. This drug therefore represents a promising candidate for repurposing to effectively treat severe sepsis and ARDS.
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影响因子：
37.8
作者：
Huang X;Dai Z;Cai L;Sun K;Cho J;Albertine KH;Malik AB;Schraufnagel DE;Zhao YY
通讯作者：
Zhao YY
影响因子：
15.9
作者：
Gong, Haixia;Rehman, Jalees;Malik, Asrar B.
通讯作者：
Malik, Asrar B.
DOI：
10.1164/rccm.200109-016oc
发表时间：
2002-07-01
影响因子：
24.7
作者：
De Backer, D;Creteur, J;Vincent, JL
通讯作者：
Vincent, JL
影响因子：
158.5
作者：
Chertow, Glenn M.;Pergola, Pablo E.;Eckardt, Kai-Uwe
通讯作者：
Eckardt, Kai-Uwe
影响因子：
158.5
作者：
Ackermann, Maximilian;Verleden, Stijn E.;Jonigk, Danny
通讯作者：
Jonigk, Danny