and Specific Aims.) Pseudomonas aeruginosa is a major pathogen in nosocomial pneumonia in normal and in immunocompromised hosts. Mucoid P. aeruginosa is the bacterium associated with chronic infections and pneumonia in patients with cystic fibrosis, particularly in the CF patients that die. The treatment of infections caused by P. aeruginosa has not lead to improved patient outcomes; a better understanding of the pathogenetic mechanisms is necessary to define new strategies for treatment. The interactions between bacterial products and alveolar defenses are important for the production of lung injury. Two bacterial products, exoenzyme S and mucoid exopolysaccharide (MEP), appear to cause lung injury. There are two Specific Aims: 1) To determine the effect of these bacterial products in vivo, P. aeruginosa strains that synthesize or cannot synthesize exoenzyme S and MEP will be utilized in a model of rat acute lung injury. These studies may determine the role of these products in lung injury and give insight into the mechanism of injury. 2) To determine the mechanisms of host defense against P. aeruginosa, alveolar macrophages and neutrophils will be manipulated and new therapies affecting host defenses will be delivered to the airspaces. Alveolar macrophages will be depleted to determine the importance of the macrophage in bacterial clearance, to assess the macrophages' production of IL-8, and to determine whether aerosolized specific IgG can opsonize P. aeruginosa optimally without the presence of the alveolar macrophage. Neutrophils will be depleted to determine the effect on bacterial clearance by an increased number of alveolar macrophages. Alveolar macrophage quantity and stimulation will be modulated by the aerosolization of liposomes complexed to expression vectors for GM-CSF. Aerosolized specific IgG will also be administered to the neutropenic rats to ascertain whether optimal opsonization occurs when only the alveolar macrophage is present. These studies may elucidate the interplay of phagocytes and immunoglobulins in the airspace.
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