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: 10393782
• 负责人: Yang Jin
• 金额: $ 0.97万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393782
• 关键词: Acids; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Anesthesia procedures; Aspirate substance; Bronchoalveolar Lavage Fluid; Caveolins; Cells; Characteristics; Complex; Critical Care; Critical Illness; Data; Development; Diagnostic; Distress; Edema; Endothelium; Epithelial; Epithelial Cells; Esophagus; Event; Exposure to; Funding; Hyperoxia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Lung; Lung Inflammation; Macrophage Activation; Mediating; Medicine; Membrane Microdomains; MicroRNAs; Modeling; Modification; Mus; Natural Immunity; Organ failure; Oxygen; Pathogenesis; Patients; Publishing; Reporting; Respiratory Failure; Signal Transduction; Sterility; Stimulus; Stomach; Syndrome; Testing; Therapeutic; Training; Trauma; Wages; Work; alveolar epithelium; base; caveolin 1; extracellular vesicles; falls; in vivo; insight; intercellular communication; microvesicles; migration; mortality; novel; post-trauma; recruit; severe injury; supplemental oxygen; systemic inflammatory response; undergraduate student

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 cellcell 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 EVs 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. This current application is a supplemental proposal to request funds for an undergraduate student who will be trained by us in summer and working on this project from June to August 2021.

抽象/总结