Oxidized glutathione regulation of epithelial sodium channels in newborn lung injury

氧化型谷胱甘肽对新生儿肺损伤中上皮钠通道的调节

• 批准号: 10187639
• 负责人: My N. Helms
• 金额: $ 38.47万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187639
• 关键词: Acute Lung Injury; Adult; Alveolar; Amiloride; Antioxidants; Apical; Attenuated; Back; Binding; Bioinformatics; Biological; Birth; Blood Circulation; C57BL/6 Mouse; Cells; Clinical; Data; Development; Disulfides; Epithelial; Epithelial Cells; Excision; Exposure to; Fetal Lung; Floods; Fluid Balance; Functional disorder; Gases; Glutathione; Glutathione Disulfide; Goals; Health; Hyperoxia; Injury; Investigation; Kinetics; Life; Liquid substance; Lung; Maps; Mass Spectrum Analysis; Measures; Modeling; Molecular; Movement; Mus; Newborn Infant; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen; Pathogenesis; Patients; Pharmacology; Phenotype; Play; Population; Post-Translational Protein Processing; Premature Infant; Probability; Process; Proteins; Public Health; Reaction; Recycling; Regulation; Research; Research Personnel; Risk; Risk Factors; Role; Signal Pathway; Site-Directed Mutagenesis; Sodium Chloride; Structure; Structure of parenchyma of lung; Sulfhydryl Compounds; Supplementation; Surface; Time; Transmembrane Domain; Water; airway epithelium; base; cell injury; disulfide bond; epithelial Na+ channel; experience; extracellular; improved; in vivo; interest; lung injury; mouse model; patch clamp; postnatal; pulmonary function; pup; sodium channel proteins

Project Summary/Abstract Epithelial sodium channels (ENaC) serve as the rate limiting step in net salt and water removal from the airspace by generating osmotic gradients for subsequent water transport. In the lung, the regulation of ENaC is fine-tuned so that a precise volume of water continually lines the airway epithelium, which keeps the lungs appropriately moist for effective gas exchange. In some patients with lung injury, it is not clear why lung ENaC fails to function. Normal ENaC activity is critically important in preterm infants, since they are born with immature lung, low levels of ENaC protein, and often require oxygen supplementation. In this study, we look at whether oxygen supplementation (hyperoxia) confounds lung injury by turning off ENaC. We use a term mouse model of hyperoxia induced oxidative stress in our studies. Our rationale is that under high oxygen, the antioxidant glutathione is oxidized to its disulfide form, termed GSSG. Our preliminary data indicates that GSSG can alter ENaC function through direct post translational modification of conserved Cys thiols on ENaC, albeit the modified Cys have not been mapped. Whether GSSG modifies ENaC under a biologically relevant model of hyperoxia induced lung injury has not been evaluated. Our goal is to delineate biologically relevant post-translational modification of lung ENaC by GSSG and determine whether lowering lung GSSG levels can improve health outcomes for preterm infants requiring oxygen supplementation.

项目摘要/摘要 上皮钠通道（ENAC）用作净盐和从空域去除水的速率限制步骤 通过产生渗透梯度以进行随后的水运输。在肺中，ENAC的调节是微调的 因此，精确的水不断地排在气道上皮，这使肺部适当地保持 潮湿以进行有效的气体交换。在某些肺损伤的患者中，尚不清楚为什么肺ENAC无法发挥作用。 正常的ENAC活性在早产儿中至关重要，因为它们出生于未成熟的肺，低水平 ENAC蛋白质，通常需要补充氧气。在这项研究中，我们研究了氧气是否 补充（高氧）通过关闭ENAC来混淆肺损伤。我们使用一个术语鼠标模型 高氧在我们的研究中诱导氧化应激。我们的理由是，在高氧气下，抗氧化剂 谷胱甘肽被氧化为其二硫键形式，称为GSSG。我们的初步数据表明GSSG可以改变 ENAC功能通过在ENAC上对保守的Cys硫醇进行直接翻译的直接转换，尽管经过修改 CYS尚未映射。 GSSG是否在生物学相关的高氧模型下修改ENAC 尚未评估诱导的肺损伤。我们的目标是描述与生物学相关的翻译后 GSSG修改肺ENAC并确定降低肺GSSG水平是否可以改善健康状况 早产儿需要补充氧气的结果。

项目成果

Regulation of hyperoxia-induced neonatal lung injury via post-translational cysteine redox modifications.

• DOI: 10.1016/j.redox.2022.102405
• 发表时间: 2022-09
• 期刊: REDOX BIOLOGY
• 影响因子: 11.4
• 作者: Zhang, Tong;Day, Nicholas J.;Gaffrey, Matthew;Weitz, Karl K.;Attah, Kwame;Mimche, Patrice N.;Paine, Robert, III;Qian, Wei-Jun;Helms, My N.
• 通讯作者: Helms, My N.

Tumor microenvironment in salivary gland carcinomas: An orchestrated state of chaos.

• DOI: 10.1016/j.oraloncology.2022.105777
• 发表时间: 2022-02
• 期刊: Oral oncology
• 影响因子: 4.8
• 作者: E. Egal;J. Scarini;R. A. de Lima-Souza;L. Lavareze;P. Fernandes;C. Emerick;Mayara Trevizol Gonçalves-Mayara-Trevizol-Gonça

High-mobility group box-1 increases epithelial sodium channel activity and inflammation via the receptor for advanced glycation end products.

高迁移率 group box-1 通过晚期糖基化终产物受体增加上皮钠通道活性和炎症。

• DOI: 10.1152/ajpcell.00291.2019
• 发表时间: 2020
• 期刊: American journal of physiology. Cell physiology
• 作者: Grant,GarettJ;Liou,TheodoreG;Paine3rd,Robert;Helms,MyN
• 通讯作者: Helms,MyN