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）： 候选人接受过重症监护和麻醉方面的培训，并具有急性肺损伤（ALI）气体交换和机械通气研究的研究背景。 他的长期目标是进一步了解ALI中气体交换受损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。 在该应用中，他提出使用基于正电子发射断层扫描（PET）的功能成像的生理研究的创新工具来测试以下假设：1）ALI中的气体交换受损是局部肺功能改变的结果，其涉及局部灌注和局部通气; 2）肺泡复张策略，如呼气末正压和复张策略，在ALI中有两个主要影响：a）恢复非通气区域的通气，或B）过度扩张已经通气的区域，并将肺灌注转移到非通气区域。 这两种效应之间的平衡决定了它们对气体交换的净效应; 3）募集和过度扩张之间的平衡也决定了募集策略是否减弱或促进与呼吸机诱导的肺损伤（VILI）相关的炎症过程。 为了验证这些假设，候选人提出追求以下特定目标（SA）：1）表征ALI患者的局部气体交换; 2）确定招募策略影响ALI患者和具有不同招募潜力的良好表征的肺损伤模型中的局部气体交换的机制; 3）确定募集策略调节与VILI相关的炎症过程的能力是否取决于募集的潜在潜力; 4）测试白三烯是否介导损伤性免疫策略导致中性粒细胞活化和与VILI相关的炎性级联反应的过程。 研究设计包括在ALI患者中进行的研究，以解决SA 1和SA 2，以及在肺损伤实验模型中进行的研究，以补充SA 2的患者数据并解决SA 3和SA 4。 所述方法利用静脉内注射的[13 N]氮的PET成像来评估局部灌注、局部分流和局部通气，并且利用[18F]氟脱氧葡萄糖的PET成像来评估局部中性粒细胞代谢活性，这是细胞炎症的指标。 该项目的健康相关性是在其潜力提供了重要的新的洞察到一个综合征的病理生理学与高发病率，死亡率和相关的医疗保健费用。 为了有效地掌握拟议的研究和优化教育体验，候选人将由具有不同背景的医生科学家和科学家组成的咨询委员会指导，他们将提供生理，形态和方法论的见解。 该研究项目将在马萨诸塞州总医院进行，并将辅之以结构化的生理调查教育课程，为候选人提供完成该项目所需的知识基础，并在其研究生涯中取得进展。 (End摘要）