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 这个应用程序的总体目标是确定导致病理性疾病的关键事件的顺序。 丙烯醛和光气吸入后引起的进展。化学性急性肺损伤（CIALI）是一种 急性呼吸窘迫综合征（ARDS）。ARDS的特征是肺泡屏障功能丧失 这导致蛋白质和嗜中性粒细胞浸润到肺泡气隙中的增加。目前，ARDS治疗 主要限于有管理的机械通气，死亡率仍然很高。死亡率受以下因素影响 患者的性别、年龄和遗传易感性，这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。死亡可能是立即的或延迟的， 这是一种复杂的细胞和肺部反应，随着时间的推移而发展，并决定了损伤的严重程度。 另一种能引起迟发性肺水肿的化学物质是光气， 第一次世界大战的武器目前，尚不清楚丙烯醛和光气是否通过相同的方法产生CIALI。 重叠机制或每种化学品特有的机制。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 潜在的损伤严重程度和死亡率。本提案的具体目标如下：1.确定 对丙烯醛诱导的急性肺损伤的敏感性和抵抗性的时间事件，2.描述关键途径 在丙烯醛诱导的CIALI进展和解决使用多组学分析，和3。比较和对比 从β-内酰胺酶基因诱导的CIALI到丙烯醛诱导的CIALI的进展。详细的时间进程分析将 评价支气管肺泡灌洗、肺组织病理学、空间脂质组学、空间代谢组学和单细胞 和丙烯醛或光气暴露后的空间转录组学。菌株特异性和性别特异性反应将 研究了确定控制疾病进展和消退的关键病理事件的顺序 丙烯醛和光气引起的急性肺损伤可能为发展 疗法