The incidence of sepsis is increasing, particularly in the elderly population. One of the most devastating complications of sepsis is the development of the acute respiratory distress syndrome (ARDS) which is characterized by the leakage of neutrophil-rich edema fluid into the lung interstitial and alveolar space and is associated with a mortality rate of at least 65 percent in patients over the age of 65. Unfortunately, the advances in intensive and supportive care of the past decade which have led to improvements in the overall survival rate in ARDS, have not affected mortality in the aged. Sepsis initiates a systemic inflammatory response which is characterized by the sequestration of leukocytes within the pulmonary vasculature. Evidence suggests that neutrophil-derived reactive oxygen metabolites contribute to sepsis-induced pulmonary dysfunction, possibly by disturbing endothelial cell- cell junctional proteins, termed """"""""cadherins."""""""" However, the relevance of these findings to the population that is most vulnerable to the lethal effects of ARDS, i.e., the elderly, remains undefined. The central hypothesis of this research proposal is that sepsis elicits neutrophil-mediated lung microvascular injury that is exacerbated in the aged. Increased tissue oxidative stress and neutrophil-mediated disruption of endothelial cell junctional proteins, termed cadherins, account for the enhanced injury response in the aging lung. In order to test this hypothesis, we will evaluate the following specific aims: 1) To define the contribution of adherent neutrophils to sepsis-induced increases in microvascular permeability, oxidative stress and disruption of endothelial junctional proteins in the lungs of aged animals; and 2) To define the contribution of reactive oxygen metabolites to the lung permeability and endothelial junctional protein dysfunction elicited by sepsis in aged animals. The isolated, perfused rat lung will be employed to define the overall pulmonary injury response in LPS- challenged, aged animals. The results of the investigations outlined in this proposal should provide insight into the mechanism(s) responsible for sepsis-induced vascular barrier disruption and the factors that enhance endothelial dysfunction in the aged.
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