Regional Lung Function in Acute Lung Injury

急性肺损伤时的局部肺功能

• 批准号: 7123884
• 负责人: Guido Musch
• 金额: $ 13.31万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-19 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123884
• 关键词: adult respiratory distress syndrome; bioimaging /biomedical imaging; clinical research; disease /disorder model; human subject; iatrogenic disease; inflammation; laboratory mouse; leukocyte activation /transformation; leukotrienes; lung imaging /visualization /scanning; lung injury; neutrophil; pathologic process; positive pressure breathing; positron emission tomography; respirators; respiratory airflow measurement; respiratory function; respiratory gas transport; sheep

DESCRIPTION (provided by applicant): The candidate is trained in Critical Care and Anesthesia and has a research background in the study of gas exchange and mechanical ventilation in Acute Lung Injury (ALI). His long-term objective is to further the understanding of the pathophysiology of the impairment of gas exchange in ALI and of the mechanisms by which mechanical ventilation affects gas exchange and the progression of lung injury. In this application he proposes to use innovative tools of physiologic investigation based on functional imaging with Positron Emission Tomography (PET) to test the following hypotheses: 1) The impairment of gas exchange in ALI is the result of alterations of regional lung function that involve both regional perfusion and regional aeration; 2) Alveolar recruiting strategies, such as Positive End-Expiratory Pressure and Recruitment Maneuvers, can have two main effects in ALI: a) restore aeration to non-aerated regions or b) overexpand regions that are already aerated and shift pulmonary perfusion toward non-aerated regions. The balance between these two effects determines their net effect on gas exchange; 3) The balance between recruitment and overexpansion also determines whether recruiting strategies attenuate or promote the inflammatory process associated with Ventilator-Induced Lung Injury (VILI). To test these hypotheses the candidate proposes to pursue the following specific aims (SA): 1) To characterize regional gas exchange in patients with ALI; 2) To identify the mechanisms by which recruiting strategies affect regional gas exchange in patients with ALI and in well-characterized lung injury models with different potential for recruitment; 3) To determine whether the ability of recruiting strategies to modulate the inflammatory process associated with VILI depends on the underlying potential for recruitment; 4) To test whether leukotrienes mediate the process by which injurious ventilatory strategies lead to neutrophil activation and to the inflammatory cascade associated with VILI. The research design includes studies in patients with ALI to address SA1 and SA2, and studies in experimental models of lung injury to complement the patient data for SA2 and to address SA3 and SA4. The methods utilize PET imaging of intravenously injected [13N]nitrogen to assess regional perfusion, regional shunt and regional ventilation, and of [18F]fluorodeoxyglucose to assess regional neutrophil metabolic activity, an index of cellular inflammation. The health-relatedness of the project is in its potential to provide significant new insight into the pathophysiology of a syndrome with high morbidity, mortality and associated healthcare costs. To effectively master the proposed research and optimize the educational experience, the candidate will be guided by an advisory committee of physician-scientists and scientists with diverse background, who will provide physiological, morphological and methodological insight. The research project will be carried out at Massachusetts General Hospital and will be complemented by a structured educational curriculum in physiologic investigation that will provide the candidate with the knowledge base that is necessary to accomplish this project and to progress in his research career. (End of Abstract)

描述(由申请人提供)： 应聘者受过重症监护和麻醉方面的培训，在急性肺损伤(ALI)的气体交换和机械通风研究方面有研究背景。他的长期目标是进一步了解ALI气体交换障碍的病理生理学，以及机械通气影响气体交换和肺损伤进展的机制。在这项应用中，他建议使用基于正电子发射断层扫描(PET)功能成像的创新生理学研究工具来检验以下假设：1)ALI的气体交换障碍是区域肺功能改变的结果，涉及区域灌注和区域充气；2)肺泡招募策略，如呼气末正压和募集动作，在ALI中可能有两个主要作用：a)恢复充气区域的充气，或b)过度扩张的已充气区域，并将肺灌注转移到非充气区域。这两种影响之间的平衡决定了它们对气体交换的净影响；3)招募和过度扩张之间的平衡还决定了招募策略是减轻还是促进与呼吸机诱导的肺损伤(VILI)相关的炎症过程。为了验证这些假说，候选人建议追求以下特定目标(SA)：1)表征ALI患者的区域气体交换；2)确定招募策略影响ALI患者和具有不同招募潜力的肺损伤模型中区域气体交换的机制；3)确定招募策略调节与VILI相关的炎症过程的能力是否取决于潜在的招募潜力；4)测试白三烯是否介导损伤性呼吸策略导致中性粒细胞激活和与VILI相关的炎症级联的过程。研究设计包括对ALI患者的研究，以解决SA1和SA2，以及在肺损伤的实验模型中的研究，以补充SA2的患者数据，并解决SA3和SA4。这些方法利用静脉注射[13N]氮的PET成像来评估区域灌注、区域分流和区域换气，并利用[18F]氟脱氧葡萄糖来评估区域中性粒细胞代谢活动，这是细胞炎症的一个指标。该项目与健康相关的潜力在于，它有可能为一种发病率、死亡率和相关医疗成本较高的综合征的病理生理学提供重要的新见解。 为了有效地掌握拟议的研究并优化教育体验，候选人将由一个由内科科学家和具有不同背景的科学家组成的咨询委员会指导，他们将提供生理、形态和方法学方面的见解。该研究项目将在马萨诸塞州总医院进行，并将辅之以生理学调查方面的结构化教育课程，该课程将为候选人提供完成该项目并在其研究生涯中取得进步所必需的知识基础。(摘要结束)