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.

项目概要 该应用程序的总体目标是确定导致病理的关键事件的顺序 吸入丙烯醛和光气后引起进展。化学性急性肺损伤（CIALI）是一种 急性呼吸窘迫综合征（ARDS）的一种形式。 ARDS 的特点是肺泡屏障功能丧失 这导致蛋白质和中性粒细胞渗入肺泡腔的数量增加。目前，ARDS治疗是 主要局限于管理机械通气，死亡率居高不下。死亡率受以下因素影响 患者的性别、年龄和遗传易感性，可以在小鼠中进行实验建模。 CIALI 的主要风险 因素是烟雾吸入，烟雾中的主要刺激物是丙烯醛。死亡可能是立即死亡，也可能是延迟死亡 来自复杂的细胞和肺部反应，这些反应随着时间的推移而进展并决定了损伤的严重程度。 另一种可引起迟发性肺水肿的化学物质是光气，它是作为一种化学物质而开发的 第一次世界大战中的武器。目前尚不清楚丙烯醛和光气是否相同产生CIAI 重叠机制或每种化学物质独特的机制。开发有效的治疗方法 干预措施，需要更多的研究来了解疾病进展和损伤解决机制 伤害和死亡的潜在严重程度。该提案有以下具体目标： 1. 确定 对丙烯醛引起的急性肺损伤的敏感性和抵抗力的时间事件，2.描绘关键途径 使用多组学分析对丙烯醛诱导的 CIALI 进展和缓解进行评估，以及 3. 比较和对比 光气诱导的 CIALI 进展为丙烯醛诱导的 CIALI。详细的时间进程分析将 评估支气管肺泡灌洗、肺组织病理学、空间脂质组学、空间代谢组学和单细胞 以及丙烯醛或光气暴露后的空间转录组学。菌株和性别特异性反应将是 调查了。确定控制疾病进展和解决的关键病理事件的顺序 丙烯醛和光气引起的急性肺损伤应该为以下疾病的发生提供机制基础： 治疗。