Acute respiratory failure (ARF) requiring mechanical ventilation (MV) affects as many as 150,000 people per year in the United States alone, resulting in a greater incidence than either colon cancer or AIDS. Associated mortality rates are staggering (45-95%), and costs are estimated in the billions of dollars. Although potentially lifesaving, evidence has implicated MV in inducing lung injury (ventilator-induced lung injury, VILI) and contributing to multiple system organ dysfunction (MSOD). Despite a growing understanding of the complex pathophysiologic events associated with MV, ARF, and MSOD, the causes of VILI remain unclear. It is known that nucleotides are 1) released into the extracellular environment in response to shear stress, and 2) regulate numerous cellular processes, including cytokine release, monocyte and fibroblast proliferation, iNOS, adhesion molecule expression, ion transport, platelet degranulation, and apoptosis. Although these processes have individually been implicated in VILI, the central role of nucleotides in orchestrating these pathways has not been studied. We have observed that purine nucleotides are released during large-volume MV; furthermore, pharmacological manipulations of nucleotide levels implicate them in VILI- associated inflammation and alveolar fluid metabolism. We hypothesize that nucleotides play a central role in VILI, and to address this we propose three specific aims: 1) measure the basal and stimulated nucleotide concentrations in the alveolar and vascular compartments in response to selected airway stimuli, 2) determine the relationship of nucleotides to pulmonary and systemic inflammation during MV, and 3) examine the effect of nucleotides on transalveolar fluid dynamics. The long-term goal of this project will be to further our understanding of the mechanisms responsible for VILI. This proposal is designed for long-term scientific success, and benefits greatly from the intense supervision and oversight provided by an established investigator with a proven track-record of successful mentorship. A detailed 5-year plan is outlined, which frames innovative scientific research, appropriate didactic coursework, technical workshops, direct laboratory supervision, and ethical training in an environment with a strong academic tradition and commitment to training clinical scientists. The proposed research and career development plan will prepare the candidate to be an independent scientific investigator in the field of lung injury.
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