The overall emphasis of Project 9 is on animal model studies of acute lung injury, both in terms of the underlying pathophysiological processes that are occurring and how they can be moderated by specific pharmacologic interventions. Several complementary animal models are used to investigate lung injuries with varying components of inflammation, lung surfactant- deficiency, and lung surfactant inactivation as contributors to pathophysiology. Biochemical, biophysical, cellular and physiological techniques are used to characterize the injury process. Special emphasis is placed on the inflammatory component of injury and polymorphonuclear leukocyte (PMN) chemotaxis and activation during injury, and how this is affected by the presence of different kinds of surfactant dysfunction (deficiency, inactivation). The mitigation of these injuries is then attempted by therapy with anti-oxidants (superoxide dismutase, SOD), exogenous surfactant, and anti-inflammatory agents (dexamethasone), to help assess the importance of different mechanisms as well as to define therapeutic potential. The project proceeds through a series of related Specific Aims involving: 1) studies of acute lung injury in neonatal piglets resulting from hyperoxia and mechanical hyperventilation, and how it is worsened by the presence of an initial surfactant-deficiency induced by in vivo lung lavage; 2) studies of how the above lung injury in piglets is mitigated by administration of therapeutic agents (exogenous surfactant, SOD, and dexamethasone) directed at specific processes occurring in the pathophysiology of injury; 3) studies of the fulminant lung injury induced in rabbits and piglets from oleic acid administration, which involves a prominent component of surfactant inactivation, and of related meconium aspiration injury in piglets; 4) investigations of exogenous lung surfactant replacement in oleic acid and meconium-injured animals with surfactant inactivation, as a stringent test of efficacy in Adult Respiratory Distress Syndrome-related acute lung injury; additional studies will also determine the effects of anti-oxidants and anti-inflammatory agents in this setting as well.
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