Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are significant causes of morbidity and mortality in the intensive care unit. The recognition of the deleterious effects of mechanical ventilation has led to increasing interest in the pathways involved in the acute inflammation and enhanced vascular permeability observed in ventilator-associated lung injury (VALI). Low tidal volume lung strategies remain the only supportive treatment of ALI/VALI with proven efficacy. Therefore, novel therapies that will specifically target mechanisms involved in barrier disruption and acute inflammation of ALI/VALI are needed. A potential mechanism of injury is the activation of the p38-MK2-HSP27 pathway leading to actin cytoskeletal rearrangement and resulting endothelial barrier dysfunction. p38 MAP Kinase is activated in response to multiple stimuli, many of which are present in patients with ALI/VALI, i.e., hypoxia, cytokines, and particularly mechanical stress. To this end, further investigation of the role of p38 MAP kinase and its downstream effectors in VALI is warranted. In this study, we will initially investigate the effects of mechanical stress on p38-MK2-HSP27 pathway expression and activation, both in a murine VALI model and an endothelial cell stretch model. Next, we will explore the effects of pharmacologic and genetic manipulation of the p38-MK2-HSP27 pathway in response to cyclic stretch in endothelial cells. Lastly, we will correlate the manipulation of the p38 MAP Kinase pathway in vivo to measures of VALI. Mechanical ventilation, although the cornerstone of treatment for many disorders, has the potential to exacerbate and cause de novo lung injury. We have identified a pathway that is relevant in mediating injury due to mechanical ventilation. We hope that further insight into this crucial pathway will help identify novel therapeutic targets. ? ? ?
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