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.
