The role of microRNA-223 in acute lung injury (ALI

microRNA-223在急性肺损伤（ALI）中的作用

• 批准号: 204424974
• 负责人: Dr. Viola Dengler
• 金额: --
• 依托单位: Department of Anesthesiology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/204424974?language=en
• 关键词: role; microRNA; 223; acute; lung

Acute lung injury (ALI) is characterized by acute hypoxemic respiratory failure in the setting of non-cardiogenic pulmonary edema. Mortality of ALI ranges between 35-60%. Among the hallmarks of ALI are activation and massive pulmonary accumulation of inflammatory cells into lungs and a disruption of the alveolar-capillary barrier function. In consequence this leads to an activation of hypoxia- and inflammation-elicited transcriptional pathways and changes in gene expression. Targeting molecular pathways that control lung inflammation during ALI may be of therapeutical potential. MicroRNAs (miRNA) are short non-coding RNAs that function as post-transcriptional gene regulators. While previous reports have implicated miRNAs in the post-transcriptional regulation of inflammatory and hypoxia-dependent gene expression, the role of miRNAs in modulating lung inflammation during ALI are essentially unknown. In pilot studies we induced ALI in mice and analyzed expression patterns of pulmonary miRNAs. These studies revealed profound increases in 10 miRNAs, with strongest induction of miR-223. Subsequent studies with pulmonary epithelial cells exposed to an in vitro model of mechanical ventilation demonstrated robust induction of miR-223, implicating a mucosal contribution of miR-223 induction. In conjunction with previous studies implicating miR-223 in dampening inflammatory responses, we hypothesize that mucosal induction of miR-223 should represent an endogenous anti-inflammatory pathway to attenuate lung inflammation during ALI. To study this hypothesis, we will examine the mechanisms of miR-223 induction during cyclic mechanical stretch in vitro, or during ALI in vivo. We will define the functional role of miR-223 during different phases of ALI and we attempt to target miR-223 for the treatment of ALI. These studies are designed to identify regulatory pathways during ALI and intend to introduce miRNA-based therapy as novel therapeutic approach into the treatment of ALI.

急性肺损伤（ALI）的特征是在非心源性肺水肿的情况下发生急性低氧性呼吸衰竭。ALI的死亡率在35- 60%之间。ALI的特征之一是炎症细胞的激活和大量肺内积聚以及肺泡-毛细血管屏障功能的破坏。因此，这导致缺氧和炎症引起的转录途径的激活和基因表达的变化。靶向控制ALI期间肺部炎症的分子通路可能具有治疗潜力。MicroRNA（miRNA）是一类短的非编码RNA，具有转录后基因调控功能。虽然先前的报道暗示了miRNAs在炎症和缺氧依赖性基因表达的转录后调节中的作用，但miRNAs在ALI期间调节肺部炎症的作用基本上是未知的。在初步研究中，我们在小鼠中诱导ALI并分析肺miRNAs的表达模式。这些研究揭示了10种miRNAs的显著增加，其中miR-223的诱导作用最强。随后对暴露于体外机械通气模型的肺上皮细胞的研究表明miR-223的稳健诱导，暗示了miR-223诱导的粘膜贡献。结合先前的研究暗示miR-223抑制炎症反应，我们假设黏膜诱导miR-223应该代表减轻ALI期间肺部炎症的内源性抗炎途径。为了研究这一假设，我们将研究miR-223在体外循环机械拉伸过程中或在体内ALI过程中的诱导机制。我们将确定miR-223在ALI不同阶段的功能作用，并尝试靶向miR-223治疗ALI。这些研究旨在确定ALI过程中的调控途径，并打算将基于miRNA的治疗作为新的治疗方法引入ALI的治疗中。