Autophagic Flux and Lysosomal Cathepsins in Neonatal Hyperoxia-induced Lung Injury

新生儿高氧引起的肺损伤中的自噬流和溶酶体组织蛋白酶

• 批准号: 9372181
• 负责人: SULE CATALTEPE
• 金额: $ 25.31万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372181
• 关键词: Acids; Affect; Alveolar Macrophages; Apoptosis; Autophagocytosis; Autophagosome; Birth Weight; Bronchopulmonary Dysplasia; Cathepsins; Cell Death; Cell Survival; Cessation of life; Chronic; Complication; Confocal Microscopy; Cysteine; Data; Detection; Digestion; Event; Evidence based treatment; Extremely Low Birth Weight Infant; Fluorescence; Fluorescence Microscopy; Fluorescence Spectroscopy; Fluorescent Probes; Future; Gel; Gestational Age; Goals; Homeostasis; Hospitals; Hydrolase; Hyperoxia; Impairment; In Vitro; Infant; Inflammation; Inflammatory; Knowledge; Label; Lead; Lung; Lung diseases; Lysosomes; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Neonatal; Neonatal Hyperoxic Injury; Neurodevelopmental Problem; Organelles; Oxidative Stress; Oxygen; Papio; Pathogenesis; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Play; Premature Birth; Premature Infant; Preventive; Process; Regulation; Reporter; Role; Testing; Therapeutic; base; biological adaptation to stress; cyanine dye 5; evidence base; experimental study; high risk; in vivo; in vivo imaging; insight; lung injury; morphometry; mouse model; new therapeutic target; novel; postnatal; preclinical study; premature; respiratory; response; tool

Abstract Bronchopulmonary dysplasia (BPD) is one of the most common and important sequelae of premature birth, affecting as many as 30% of infants with birth weights less than 1500 g. BPD rates have been increasing among premature infants with gestational ages less than 28 weeks due to increasing survival of extremely low birth weight infants. Infants with severe BPD often require respiratory support after discharge from the hospital and suffer from consequences of chronic respiratory morbidity throughout their lives. They are also at higher risk of neurodevelopmental problems and death. Currently, there is a shortage of evidence-based safe treatments for BPD. Autophagy is a crucial catabolic pathway for cellular homeostasis. During autophagy, cytosolic substrates or impaired organelles are enclosed in autophagosomes, and transferred to lysosomes for digestion by cathepsins and other acid hydrolases. Autophagy is induced as an important part of the mammalian stress response and is believed to represent a cytoprotective response under most circumstances, but excessive or aberrant activation of autophagy can also lead to cell death. While molecular mechanisms that regulate the formation of autophagosome are well studied, the regulation of late digestive steps of autophagy remain relatively uncharacterized. Emerging data suggest an essential role for lysosomal cysteine cathepsins in regulation and execution of autophagy. Autophagy can be activated by hyperoxia exposure of the lung, which is an important factor in the pathogenesis of BPD. However, the potential role of autophagy in BPD remains to be elucidated. Our studies have demonstrated increased activity of lysosomal cysteine cathepsins in murine and baboon lungs with BPD. The goal of this proposal is to test the hypothesis that autophagic flux induces lysosomal cysteine cathepsin activation and plays a maladaptive role in neonatal hyperoxia-induced lung injury (nHILI). The proposed studies will examine the role of autophagic flux in lysosomal cysteine cathepsin activation and determine whether autophagy-deficient mice are protected from nHILI. They will also explore whether autophagic flux can be monitored with a fluorescent-labeled cathepsin activity based probe in a murine model of nHILI. Overall, these studies should provide important insights into the role of autophagy and cysteine cathepsin activation in nHILI, which can be exploited in future studies to identify new therapeutic targets for BPD. They also have the potential to identify a novel tool for dynamic monitoring of autophagic flux in nHILI.

摘要 支气管肺发育不良（BPD）是早产最常见和最重要的后遗症之一， 影响多达30%的出生体重低于1500克的婴儿。BPD率一直在上升 在胎龄小于28周的早产儿中， 婴儿出生体重患有严重BPD的婴儿在出院后通常需要呼吸支持 并在其一生中遭受慢性呼吸道疾病的后果。他们也在更高的 神经发育问题和死亡的风险。目前，缺乏循证安全的 BPD的治疗自噬是维持细胞内环境稳定的重要代谢途径。在自噬过程中， 细胞溶质底物或受损的细胞器被包裹在自噬体中，并转移到溶酶体中， 通过组织蛋白酶和其它酸性水解酶消化。自噬被诱导为细胞凋亡的重要组成部分， 哺乳动物应激反应并被认为在大多数情况下代表细胞保护反应， 但过度或异常的自噬激活也可导致细胞死亡。虽然分子机制 调节自噬体形成的机制已经得到了很好的研究， 自噬仍然相对未被表征。新出现的数据表明溶酶体半胱氨酸的重要作用 组织蛋白酶在调节和执行自噬中的作用。自噬可以被高氧暴露激活， 肺是BPD发病的重要因素。然而，自噬在BPD中的潜在作用 仍有待阐明。我们的研究表明，溶酶体半胱氨酸组织蛋白酶的活性增加， 在小鼠和狒狒肺中的BPD。这个提议的目的是检验自噬流 诱导溶酶体半胱氨酸组织蛋白酶激活，并在新生儿高氧诱导的 肺损伤（nHILI）。拟议的研究将检查自噬通量在溶酶体半胱氨酸中的作用。 组织蛋白酶激活并确定自噬缺陷小鼠是否受到nHILI保护。他们还将 探索是否可以用荧光标记的基于组织蛋白酶活性的探针监测自噬通量， nHILI的鼠模型。总的来说，这些研究应该为自噬的作用提供重要的见解 和半胱氨酸组织蛋白酶激活，这可以在未来的研究中利用，以确定新的治疗方法， BPD的目标他们也有可能确定一个新的工具，动态监测自噬通量 在nHILI。