Regional Lung Function in Acute Lung Injury

候选人接受过重症监护和麻醉方面的培训，并具有气体研究的研究背景 在急性肺损伤（AL 1）中的置换和机械通气。他的长期目标是进一步了解 急性淋巴细胞白血病气体交换损伤的病理生理学和机械性 通气影响气体交换和肺损伤的进展。在本申请中，他建议使用创新的 基于正电子发射断层扫描（PET）功能成像的生理研究工具， 以下假设：1）AL 1中气体交换的损害是局部肺功能改变的结果， 包括局部灌注和局部通气; 2）肺泡募集策略，如呼气末正压通气 压力和复张机动在急性肺损伤中有两个主要作用：a）恢复非通气区域的通气， 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）补充和 过度扩张也决定了募集策略是否会减弱或促进相关的炎症过程 呼吸机诱导性肺损伤（VILI）为了验证这些假设，候选人建议进行以下研究 特定目的（SA）：1）描述ALL患者的局部气体交换特征; 2）通过以下方法确定机制： 哪种招募策略影响AL 1患者和特征明确的肺损伤患者的局部气体交换 3）确定招募策略是否能够调节 与VILI相关的炎症过程取决于潜在的募集潜力;和4）为了测试 白三烯是否介导了有害的免疫策略导致中性粒细胞活化的过程， 与VILI相关的炎症级联反应。研究设计包括在ALL患者中进行的研究，以解决 SA 1和SA 2，以及肺损伤实验模型中的研究，以补充SA 2的患者数据，并解决 SA 3和SA 4。该方法利用静脉注射的[13 N]氮的PET成像来评估局部灌注， 局部分流和局部通气，以及[lSF]氟脱氧葡萄糖，以评估局部中性粒细胞代谢活性， 细胞炎症的指标。该项目的健康相关性在于它有可能提供重要的新的 深入了解具有高发病率、死亡率和相关医疗费用的综合征的病理生理学。 为了有效地掌握拟议的研究和优化教育经验，候选人将被引导， 一个咨询委员会的医生，科学家和科学家与不同的背景，谁将提供生理， 形态学和方法论的洞察力。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， 候选人的知识基础，是必要的，以完成这个项目，并在他的研究生涯的进展。

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 (ALl). His long-term objective is to further the understanding of the pathophysiology of the impairment of gas exchange in ALl 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 ALl 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 ALl: 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 ALl; 2) To identify the mechanisms by which recruiting strategies affect regional gas exchange in patients with ALl 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; and 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 ALl 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 [lSF]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.