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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL049810-01A1
Application #
2225856
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1994-04-15
Project End
1999-03-31
Budget Start
1994-04-15
Budget End
1995-03-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kurahashi, Kiyoyasu; Sawa, Teiji; Ota, Maria et al. (2009) Depletion of phagocytes in the reticuloendothelial system causes increased inflammation and mortality in rabbits with Pseudomonas aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol 296:L198-209
Ernst, E J; Hashimoto, S; Guglielmo, J et al. (1999) Effects of antibiotic therapy on Pseudomonas aeruginosa-induced lung injury in a rat model. Antimicrob Agents Chemother 43:2389-94
Miyazaki, H; Broaddus, V C; Wiener-Kronish, J P et al. (1999) The effects of two antiinflammatory pretreatments on bacterial-induced lung injury. Anesthesiology 90:1650-62
Kurahashi, K; Kajikawa, O; Sawa, T et al. (1999) Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia. J Clin Invest 104:743-50
Sawa, T; Kurahashi, K; Ohara, M et al. (1998) Evaluation of antimicrobial and lipopolysaccharide-neutralizing effects of a synthetic CAP18 fragment against Pseudomonas aeruginosa in a mouse model. Antimicrob Agents Chemother 42:3269-75
Sawa, T; Ohara, M; Kurahashi, K et al. (1998) In vitro cellular toxicity predicts Pseudomonas aeruginosa virulence in lung infections. Infect Immun 66:3242-9
Pittet, J F; Kudoh, I; Wiener-Kronish, J P (1998) Endothelial exposure to Pseudomonas aeruginosa proteases increases the vulnerability of the alveolar epithelium to a second injury. Am J Respir Cell Mol Biol 18:129-35
Ohara, M; Sawa, T; Kurahashi, K et al. (1998) Induction of cyclooxygenase-2 in alveolar macrophages after acid aspiration: selective cyclooxygenase-2 blockade reduces interleukin-6 production. Anesthesiology 88:1014-22
McElroy, M C; Wiener-Kronish, J P; Miyazaki, H et al. (1997) Nitric oxide attenuates lung endothelial injury caused by sublethal hyperoxia in rats. Am J Physiol 272:L631-8
Finck-Barbancon, V; Goranson, J; Zhu, L et al. (1997) ExoU expression by Pseudomonas aeruginosa correlates with acute cytotoxicity and epithelial injury. Mol Microbiol 25:547-57

Showing the most recent 10 out of 21 publications