Abstract
Acute respiratory distress syndrome (ARDS) is a devastating syndrome responsible for significant morbidity and mortality. Diffuse alveolar epithelial cell death, including but not limited to apoptosis and necroptosis, is one of the hallmarks of ARDS. Currently, no detectable markers can reflect this feature of ARDS. Hyperoxia-induced lung injury is a well-established murine model that mimics human ARDS. We found that hyperoxia and its derivative, reactive oxygen species (ROS), upregulate miR-185-5p, but not miR-185-3p, in alveolar cells. This observation is particularly more significant in alveolar type II (ATII) than alveolar type I (ATI) cells. Functionally, miR-185-5p promotes expression and activation of both receptor-interacting kinase I (RIPK1) and receptor-interacting kinase III (RIPK3), leading to phosphorylation of mixed lineage kinase domain-like (MLKL) and necroptosis. MiR-185-5p regulates this process probably via suppressing FADD and caspase-8 which are both necroptosis inhibitors. Furthermore, miR-185-5p also promotes intrinsic apoptosis, reflected by enhancing caspase-3/7 and 9 activity. Importantly, extracellular vesicle (EV)-containing miR-185-5p, but not free miR-185-5p, is detectable and significantly elevated after hyperoxia-induced cell death, both in vitro and in vivo. Collectively, hyperoxia-induced miR-185-5p regulates both necroptosis and apoptosis in ATII cells. The extracellular level of EV-cargo miR-185-5p is elevated in the setting of profound epithelial cell death.
Highlights
Acute respiratory distress syndrome (ARDS) is a devastating syndrome responsible for significant morbidity and mortality
We found MLE15 cells transfected with miR-185-5p mimics (0.04 nmol for 24 h) expressed an increased level in relative phospho-mixed lineage kinase domain-like (MLKL) expression when compared to cells treated with control mimics; Consistently, MLE15 cells transfected with miR185-5p inhibitors (0.04 nmol for 24 h) showed a decrease in relative phospho-MLKL expression (Fig. 4a, b)
We found that miR-185-5p promotes necroptosis in alveolar type II cells via modulating FADD/caspase-8 pathways
Summary
Acute respiratory distress syndrome (ARDS) is a devastating syndrome responsible for significant morbidity and mortality. Its mild form was formerly named acute lung injury (ALI). Non-cardiogenic pulmonary edema, vascular leakage, inflammation, lung epithelial cell injury, and dysfunction are key features of ARDS/ALI. Despite recent progress in protective ventilation strategies, the fundamental pathogenesis of ALI/ARDS remains poorly understood, impeding the development of highly effective prevention and/or treatment strategies. Hyperoxia-induced lung injury (HALI) is a wellestablished murine model that mimics human ARDS, which has been extensively used to better understand the pathogenesis of ARDS1. One of the prominent features of ARDS is alveolar epithelial cell death[2]. Hyperoxia is known to induce lung epithelial cell death by mechanisms such as necrosis, apoptosis, necroptosis, and autophagic cell death[3]. The molecular mechanisms behind hyperoxia-induced alveolar cell death remains incompletely understood, requiring further investigation. There is no detectable markers which reflect the undergoing alveolar cell death, missing an opportunity to develop early diagnostics and therapeutics
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