For unknown reasons, patients wit ARDS have increased interleukin (IL-1), neutrophils, hydrogen peroxide (H202) and edema in their lungs and evidence of an altered lung and systemic oxidant-antioxidant balance. Our hypothesis is that toxic O2 radicals derived from xanthine oxidase (XO) and/or neutrophils contribute to lung leak in rats given IL-1 or ARDS patients. O2 radicals cause leak by peroxidizing lipids, oxidizing glutathione (GSH), inactivating antiprotease, and depleting vitamin E- processes which contribute to lung leak and further activate neutrophils. We propose that these events are associated with extracellular increases in SOD, catalase, XO, myeloperoxidase (MPO), GSSG and H2) which reflect and alter these processes. Our preliminary data supports this premise. Intratracheal IL-1 caused neutrophil accumulation and a neutrophil-dependent leak in lungs of intact rats which is associated with increased lung GSSG levels. Leak was decreased by treatment with DMSO, supercritical fluid aerosolized vitamin E, liposomal encapsulated PGE, or N-acetylcysteine-- in some cases even when these interventions are given after the IL-1 insult. IL-1 also caused leak and perfusate catalase increases in isolated lungs perfused with normal neutrophils but not heat-inactivated neutrophils which fail to make 02 radicals. In parallel, MnSOD, catalase and elastase-alpha1Pi complexes were increased in the blood of septic patients with ARDS compared to septic patients without ARDS. Our immediate specific aims are to determine the mechanisms responsible for lung leak in intact rats given IL-1 intratracheally or isolated IL-1 treated rat lungs perfused with neutrophils. Our investigations involve determination of the relationship of neutrophils, XO, oxidative injury and the appearance of extracellular markers in lungs treated with IL-1. Investigation also involves study of the effect of a carefully selected sequence of interventions that not only define these processes but also can potentially be used for treating ARDS patients. Parallel studies will evaluate neutrophils and serum from patients with and at risk for ARDS as a function of ARDS progression and intervention. The significance of these studies is (1) to improve understanding of fundamental mechanisms responsible for acute lung injury, (2) to gain new information regarding the predictive and functional value of extracellular markers and (3) to identify and define interventions which might be useful in treating or preventing ARDS.
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