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

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 在胎龄低于28周的早产儿中，由于存活率极低而增加 出生体重婴儿。患有严重BPD的婴儿出院后通常需要呼吸支持。 并终生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，以循证为基础的外管局存在不足。 BPD的治疗。自噬是细胞内稳态的重要分解代谢途径。在自噬过程中， 胞浆底物或受损的细胞器被包裹在自噬小体中，并转移到溶酶体中 被组织蛋白酶和其他酸性水解酶消化。自噬是自噬的一个重要组成部分。 哺乳动物的应激反应，据信在大多数情况下代表一种细胞保护反应， 但自噬的过度或异常激活也会导致细胞死亡。虽然分子机制 对自噬形成的调控研究较多，对自噬后期消化步骤的调控研究较多。 自噬仍然是相对不具特征的。新出现的数据表明溶酶体半胱氨酸的重要作用 自噬的调节和执行中的组织蛋白。自噬可以通过暴露在高氧环境中的 肺是BPD发病机制中的重要因素。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的活性增加。 在患有BPD的小鼠和狒狒肺中。这一提议的目标是检验自噬通量的假设 诱导溶酶体半胱氨酸组织蛋白酶激活在新生儿高氧诱导的适应不良中的作用 肺损伤(NHILI)。拟议的研究将检验自噬通量在溶酶体半胱氨酸中的作用。 并确定自噬缺陷小鼠是否受到nHILI的保护。他们还将 探讨是否可以用荧光标记的组织蛋白酶活性探针来监测自噬通量 NHILI的小鼠模型。总体而言，这些研究应该会为自噬的作用提供重要的见解 和半胱氨酸组织蛋白酶在nHILI中的激活，这可以在未来的研究中被利用来寻找新的治疗方法 石油日产量的目标。它们还有可能确定一种动态监测自噬通量的新工具 在nhili。

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.