Pathophysiological Mechanisms of Chemical-Induced Acute Lung Injury

化学引起的急性肺损伤的病理生理机制

• 批准号: 10708438
• 负责人: George Douglas Leikauf
• 金额: $ 49.93万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708438
• 关键词: 129X1/SvJ Mouse; Accidents; Acrolein; Acute Lung Injury; Acute Respiratory Distress Syndrome; Age; Air; Alveolar; Bronchoalveolar Lavage; Carbon; Cell Death; Cells; Cessation of life; Chemical Weapons; Chemicals; Complex; Critical Pathways; Development; Diagnosis; Disease Progression; Endothelium; Etiology; Event; Experimental Models; Exposure to; Eye; Female; Freezing; Gases; Genetic Predisposition to Disease; Global Warming; Goals; Hazardous Chemicals; Histopathology; Infiltration; Inhalation; Injury; Investigation; Irritants; Knowledge; Lipids; Lung; Measures; Mechanical ventilation; Methods; Molecular; Molecular Analysis; Molecular Target; Mouse Strains; Mus; Neutrophil Infiltration; Outcomes Research; Oxygen; Partial Pressure; Pathologic; Pathway interactions; Patients; Phosgene; Predisposition; Prevention; Proteins; Public Health; Pulmonary Edema; Reaction; Research; Resistance; Resolution; Respiratory System; Risk Factors; SM/J Mouse; Severities; Smoke; Structure; Terrorism; Testing; Therapeutic Intervention; Time; Transcript; Wildfire; World War I; alveolar epithelium; design; innovation; insight; irritation; lipidomics; lung injury; macromolecule; male; metabolomics; mortality; multiple omics; research clinical testing; response; sex; single-cell RNA sequencing; skin burn; smoke inhalation; therapeutically effective; therapy development; transcriptomics

Project Summary The overall goal of this application is to determine the sequence of key events that leads to the pathological progression elicited after acrolein and phosgene inhalation. Chemically-induced acute lung injury (CIALI) is a form of acute respiratory distress syndrome (ARDS). ARDS is characterized by loss of alveolar barrier function that leads to increased protein and neutrophil infiltration into the alveolar air space. Currently, ARDS therapy is mainly limited to managed mechanical ventilation, and the mortality rate remains high. Mortality is influenced by sex, age, and genetic susceptibility in patients, which can be experimentally modeled in mice. A major CIALI risk factor is smoke inhalation and the main irritant in smoke is acrolein. Death can be immediate or delayed resulting from a complex cellular and pulmonary responses that progress with time and dictate the severity of the injury. Another chemical that can induce delayed pulmonary edema is phosgene, which was develop as a chemical weapon in World War I. Currently, it is unknown whether acrolein and phosgene produce CIALI by the same overlapping mechanisms or by mechanisms unique to each chemical. To develop effective therapeutic interventions, more studies are needed to understand the disease-progression and injury-resolution mechanisms underlying severity of injury and mortality. This proposal has the following Specific Aims: 1. Determine the temporal events of sensitivity and resistance to acrolein-induced acute lung injury, 2. Delineate critical pathways in acrolein-induced CIALI progression and resolution using multiomic analyses, and 3. Compare and contrast the progression of phosgene-induced CIALI to that of acrolein-induced CIALI. Detailed time course analyses will evaluate bronchoalveolar lavage, lung histopathology, spatial lipidomics, spatial metabolomics and single-cell and spatial transcriptomics following acrolein or phosgene exposure. Strain- and sex-specific responses will be investigated. Determining the sequence of key pathological events controlling the progression and resolution of acute lung injury elicited by acrolein and phosgene should provide a mechanistic basis for the development of therapy.

项目摘要 该应用程序的总体目标是确定导致病理学的关键事件的顺序 丙烯醛和磷光吸入后引起进展。化学诱导的急性肺损伤（CIALI）是 急性呼吸窘迫综合征（ARDS）的形式。 ARD的特征是肺泡屏障功能的丧失 这导致蛋白质和中性粒细胞浸润增加到肺泡空气空间。目前，ARDS治疗是 主要限于托管机械通气，死亡率仍然很高。死亡率受 患者的性别，年龄和遗传敏感性可以在小鼠中实验建模。主要的ciali风险 因子是吸入烟雾，烟雾中的主要刺激性是丙烯醛。死亡可能是立即或延迟导致的 从随时间发展并决定损伤的严重程度的复杂细胞和肺反应。 另一种可能诱导延迟肺水肿的化学物质是磷酸盐，该化学物质是作为化学物质发展的 第一次世界大战中的武器。目前，尚不清楚丙烯醛和铜绿是否同时产生ciali 重叠机制或每种化学物质独有的机制。发展有效的治疗 干预措施，需要更多的研究来了解疾病产生和损伤的机制 受伤和死亡率的严重程度。该建议具有以下具体目的：1。确定 敏感性和对丙烯醛诱导的急性肺损伤的敏感性和抗性的时间事件，2。描绘临界途径 在丙烯醛诱导的CIALI进展和分辨率中，使用多媒体分析，3。 磷酸化诱导的ciali的进展到丙烯醛诱导的ciali的进展。详细的时间课程分析将 评估支气管肺泡灌洗，肺部组织病理学，空间脂质组学，空间代谢组学和单细胞 和丙烯醛或磷酸盐暴露后的空间转录组学。应变和特定性别的反应将是 调查。确定控制关键病理事件的顺序，以控制 丙烯林和磷酸引起的急性肺损伤应为发展提供机械基础 治疗。