Regulation of Ozone Induced Neutrophilic Lung Inflammation by ATP Synthase Complex V

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Inflammation is a protective response against physical or chemical perturbation of the host environment. Ozone is a toxic environmental pollutant and is attributed to cause neutrophilic lung inflammation and injury. Although lungs are usually patrolled by resident neutrophils, a fulminant neutrophil response in the lungs is associated with disruption of the alveolar capillary barrier and impaired lung function. The fundamental mechanisms of neutrophil recruitment and their role in ozone-induced lung inflammation are not fully understood. Thus, the primary thrust of my research is to understand the fundamental mechanisms of neutrophil activation and their role in lung inflammation using an array of in vitro, intravital and in vivo cell and molecular methods. I have recently developed and characterized a sophisticated model of lung inflammation induced with low dose (0.05 ppm) ozone in C57BL/6NJ strain mice. This ozone-induced lung inflammation is characterized by marked neutrophil and eosinophil cell death, formation of nuclear extracellular traps (NETs), platelet clumping and reduced alveolar contraction. We made a novel observation of expression of the ß subunit of ATP synthase complex V (ATPS-V) in the lung vasculature and alveolar septa of ozone-exposed mice. But the fundamental role of ATPS-V in lung inflammation specifically neutrophil migration and alveolar permeability is not known. Considering that there is previous evidence of role of ATPS-V in neutrophil migration, my short term objectives are to use this model to address the following fundamental questions: 1. Does ATPS-V enhance ozone induced acute lung neutrophil migration and activation? 2. Does ATPS-V recover ozone induced alveolar contractile dynamics? 3. Does ATPS-V protect against ozone induced compromised alveolar barrier? I will use my expertise in the use of advanced methods such as microscopy enabled cell phenotyping, computed tomography (CT), synchrotron x-ray multiple image radiography (MIR), intravital lung imaging and micro positron emission tomography (PET-CT) to address these fundamental questions. The current grant proposes the utilization of cross-disciplinary natural sciences in order to reveal fundamental effects of ozone inhaled with the air. The data obtained from the proposed experiments will enhance our understanding of mechanisms of lung inflammation induced with low dose exposure to ozone. The findings will elaborate on the hitherto unknown role of ATPS-V in lung inflammation specifically neutrophil migration, alveolar capillary permeability and alveolar contractile function. The studies will further provide new imaging and in vivo tools to study organ physiology. The fundamental data may, at some point, influence environmental policies in Canada. Lastly, there is contribution to the HQP training using advanced and unique imaging tools at Canada's only Synchrotron facility.