A recent randomized clinical trial by the Acute Respiratory Distress Syndrome (ARDS) Network demonstrated a 22% reduction in mortality in patients by simply reducing the tidal volume for mechanical ventilation from the conventional setting of 12 ml/kg to a lower setting of 6 ml/kg. This dramatic decrease in morbidity and mortality has stimulated significant interest in the mechanisms of ventilator-induced lung injury (VILI) and the development of lung protective strategies. Rapid repair of the alveolar epithelium following injury is crucial for restoration of barrier function and gas exchange, while restoration of the airway epithelium is important to prevent fibroproliferation and occlusion of the airways and to reduce the possibility of infection. The present proposal is designed to address the hypothesis that increased mechanical tension inhibits healing of injured pulmonary epithelium. This is important because epithelial repair may be inhibited in patients with acute lung injury in whom overdistention of lung epithelium occurs during positive pressure mechanical ventilation. The majority of recent studies examining ventilator-induced lung injury have focused on how mechanical forces activate proinflammatory pathways or induce additional injury. Our study explores the role of mechanical forces during the reparative phase following injury. Mechanisms by which mechanical strain inhibits wound repair will be examined using an in vitro model of alveolar and airway epithelial cells cultured on elastic substrates. The hypothesis that mechanical strain alters localized levels of mechanical tension that drive wound repair will be tested. Atomic force microscopy will be used to measure localized cell stiffness. Changes in cytoskeletal remodeling, microtubule growth, focal adhesions, and other structural components of wound healing in response to mechanical strain will be examined. Mechanotransduction pathways involving Rho GTPases and cytoskeletal remodeling during wound repair will be investigated. Since there is some uncertainty regarding the degree of deformation of airways in vivo, mechanical strain will be measured in mechanically ventilated rats using microfocal X-ray imaging of tantalum-coated airways. The proposed work will provide a foundation for understanding the role of mechanical forces and ventilator settings in epithelial repair mechanisms following lung injury.
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