VENTILATOR-ASSOCIATED ALVEOLAR EPITHELIAL INJURY

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DESCRIPTION: (provided by applicant): Recent clinical studies have found that low tidal volume ventilation dramatically decreases mortality from the acute respiratory distress syndrome; however, the mechanism of the protective effect is not completely understood. The overall hypothesis of the proposed studies is that high tidal volumes injure the alveolar epithelium by inducing stretch-responsive changes in lung macrophages and alveolar epithelial cells that promote inflammation and impair alveolar epithelial sodium and fluid transport. Preservation of alveolar fluid transport is both a marker of epithelial injury and a mechanism by which ventilator-associated lung injury is attenuated because 1) flooding of the alveolar airspace contributes to the overdistention and injury of other, air-filled alveoli, and 2) airspace edema inactivates surfactant promoting atelectasis and lung volume loss. Aim 1 will determine whether mechanical ventilation activates alveolar and interstitial macropha-es in normal lungs and if macrophages are important in the amplification of alveolar epithelial and lung endothelial injury in a clinically relevant rat model of ventilator-associated lung injury. Preliminary data indicate that higher tidal volumes within a clinically- applicable range induce a greater increase in plasma IL-113 in this model. Alveolar epithelial injury as measured by biochemical markers, functional markers, and histology is incrementally reduced as tidal volume is decreased from 12 ml/kg to 3 ml/kg, at similar levels of end-expiratory pressure. Aim 2 will determine whether products of macrophage activation inhibit alveolar epithelial fluid transport and whether impaired alveolar epithelial sodium and fluid transport is important in the pathogenesis of VALI in murine models. Preliminary data show that alveolar epithelial sodium and fluid transport decrease as tidal volume is increased. Aim 3 will determine whether the activation of macrophage-derived TGF-beta2 by the epithelial integrin alpha1beta2 is important to alveolar epithelial and lung endothelial injury in ventilator-associated lung injury. Preliminary data show that the absence of beta2 integrin confers protection from acute lung injury. The environment at the Cardiovascular Research Institute, including mentoring, laboratory facilities, scientific conferences, and formal coursework will provide me with an ideal setting to further advance my skills as an investigator. This research and comprehensive career development plan will prepare me to become an independent investigator in the mechanisms of alveolar epithelial injury and ventilator-associated lung injury.