Mechanistic insights of inflammation and organ failure after trauma or critical illness

创伤或危重疾病后炎症和器官衰竭的机制见解

• 批准号: 9894815
• 负责人: Yang Jin
• 金额: $ 31.35万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894815
• 关键词: Acids; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Alveolar Cell; Alveolar Macrophages; Anesthesia procedures; Aspirate substance; Bronchoalveolar Lavage Fluid; Caveolins; Cells; Characteristics; Complex; Critical Care; Critical Illness; Data; Development; Diagnostic; Distress; Edema; Encapsulated; Endothelium; Epithelial; Epithelial Cells; Epithelium; Esophagus; Event; Exposure to; Hyperoxia; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Lung; Lung Inflammation; Macrophage Activation; Mediating; Medicine; Membrane Microdomains; Methods; MicroRNAs; Modeling; Modification; Mus; Natural Immunity; Organ failure; Oxygen; Pathogenesis; Patients; Proteins; Publishing; Pulmonary Inflammation; RNA; Regulatory Pathway; Reporting; Research; Respiratory Failure; Role; Serum; Signal Pathway; Signal Transduction; Sterility; Stimulus; Stomach; Syndrome; Testing; Therapeutic; Trauma; Work; alveolar epithelium; base; caveolin 1; clinically significant; extracellular vesicles; falls; in vivo; innovation; insight; intercellular communication; macrophage; microvesicles; migration; mortality; next generation sequencing; novel; novel diagnostics; novel therapeutics; post-trauma; recruit; response; severe injury; systemic inflammatory response

Abstract/Summary Aspiration of non-infectious gastro-esophageal contents and/or exposure to high concentrations of supplemental oxygen are common events in trauma, anesthetized and/or other critically ill patients. Some of these patients will develop a more serious and protracted pulmonary or systemic inflammatory response leading to acute lung injury (ALI) or worse, acute respiratory distress syndrome (ARDS). Despite recent advances in critical care medicine, overall mortality from ARDS remains unacceptably high, reflecting the lack of specific therapies. Currently, the pathogenesis of this devastating syndrome remains incompletely understood, particularly after the “non-infectious” or “sterile” stimuli as mentioned above. The characteristic features of ALI/ARDS include an intense inflammatory response, severe injury to the epithelial / endothelial barrier and alveolar edema. Recent evidence suggests that type I alveolar epithelial (ATI) cell have previously unrecognized functions in innate immunity and are underappreciated players in lung cell- cell cross-talk. Based on our published and preliminary data, we propose that ATI cell-derived microvesicles (ATI-MVs) mediate the intercellular communication between ATI cells and alveolar macrophages (AMs) by the shuttling of selective miRNAs, thus broadcasting distress signals to the recipient cells and initiating the inflammatory cascades. In our previous work, we have reported that epithelial extracellular vesicles (EVs) are inducible and detectable in both mouse broncho-alveolar lavage fluid (BALF). After exposure to aspirated acid or hyperoxia (sterile model of ALI), most of the induced E Vs originate from living ATI epithelial cells and fall into the range of microvesicles (MVs). We further showed that MV-shuttling miRNAs promoted classic macrophage activation and migration in vitro and lung inflammation in vivo. Lipid raft protein caveolin-1 (cav-1) facilitates the selection of miRNA complex in the MVs. Based on our published and the supporting data, we hypothesize that the type I alveolar epithelial MVs mediate non-infectious stimuli-associated inflammation via promoting macrophage activation and recruitment through MV-miRNAs. We also hypothesize that the stimuli-induced cav-1 / hnRNPA2B1 interaction and modification regulate the incorporation of selective miRNAs into MVs. We will test our hypotheses in the following specific aims. In aim I: we will characterize the secretion of MV-miRNAs and their target cells in the presence of non-infectious stimuli. In aim II, we will determine the mechanisms of the miRNA selection in MVs. In aim III, we will determine the functions of MV-miRNAs after non-infectious stimuli.

摘要/概要 吸入非感染性胃食管内容物和/或暴露于高浓度的 补充氧气是创伤、麻醉和/或其它危重病人中常见的事件。一些 这些患者将发生更严重和持久的肺部或全身炎症反应， 急性肺损伤（ALI）或更严重的急性呼吸窘迫综合征（ARDS）。尽管最近的进展， 根据重症监护医学，ARDS的总体死亡率仍然高得不可接受，反映了缺乏特异性的 治疗目前，这种破坏性综合征的发病机制仍不完全清楚， 特别是在如上所述的“非感染性”或“无菌”刺激之后。 ALI/ARDS的特征性特征包括强烈的炎症反应、严重的肺损伤和严重的呼吸道损伤。 上皮/内皮屏障和肺泡水肿。最近的证据表明，I型肺泡上皮细胞（ATI） 细胞在先天免疫中具有以前未被认识到的功能，并且在肺细胞中是未被认识到的参与者， 细胞串扰。基于我们发表的和初步的数据，我们提出ATI细胞衍生的微泡 （ATI-MVs）介导ATI细胞和肺泡巨噬细胞（AM）之间的细胞间通讯， 选择性的miRNAs穿梭，从而向受体细胞广播遇险信号，并启动 炎症级联反应 在我们以前的工作中，我们已经报道了上皮细胞外囊泡（EV）是可诱导的和可检测的 小鼠支气管肺泡灌洗液（BALF）中。暴露于吸入酸或高氧（无菌）后 在ALI模型中，大多数诱导的EV来源于活的ATI上皮细胞，并落入 微泡（MV）。我们进一步发现MV穿梭miRNAs促进经典的巨噬细胞活化， 以及体外迁移和体内肺部炎症。脂筏蛋白小窝蛋白-1（caveolin-1，cav-1 在MV中的miRNA复合物。根据我们发表的和支持性的数据，我们假设I型糖尿病是一种 肺泡上皮MVs通过促进巨噬细胞介导非感染性刺激相关炎症 通过MV-miRNA激活和募集。我们还假设刺激诱导的cav-1 / hnRNPA 2B 1相互作用和修饰调节选择性miRNA掺入MV。我们将测试 我们的假设在以下具体目标。在目标I中：我们将表征MV-miRNA的分泌及其在细胞中的表达。 在非感染性刺激存在下的靶细胞。在目标II中，我们将确定miRNA的作用机制， 选择MV。在目的III中，我们将确定MV-miRNA在非感染性刺激后的功能。