The adult respiratory distress symdrome (ARDS) is a major cause of morbidity and mortality in critically ill patients. In vitro observations and animal model studies suggest activated neutrophils contribute significantly to the inflammatory injury of ARDS. Neutrophils in ARDS have demonstrated increased oxidative metabolism as defined by chemiluminescence, superoxide production, and hupochlorous acid production. Such """"""""primed neutrophils"""""""" may potentiate pulmonary endothelial damage through enhanced oxidative response. The applicant will study the kinetics and components of the respiratory burst enzyme in neutrophils of ARDS patients to determine if differnces from normal resting neutrophils exist. In addition, he will pursue the biochemical mechanisms responsible for meutrophil priming in ARDS. Phase I of the proposal will consist of: 1) graduate level course work to learn fundamental principles of biochemistry, immunology, and molecular biology required to carry out the project; 2) rotations through two laboratories, other than that of the sponsor, to learn techniques in lipid biochemistry and flow cytometry; and 3) initial work in the sponsor's laboratory to gather preliminary data on priming of neutrophils in ARDS upon which to base a detailed research plan for Phase II. A formal proposal for Phase II will be prepared and subjected to faculty review. In Phase II, the applicant will study 1) the mechanism of priming of neutrophils in ARDS; and 2) the role of physiologic mediators in the priming of neutrophils in ARDS. To accomplish these aims, he will examine the relationship of a unique phospholipase C-mediated metabolic pathway to the events of neutrophil priming in ARDS. He will also apply these techniques to the effects of physiologic stimuli on neutrophil priming as a model to explore the pathogenesis of ARDS.
| McPhail, L C; Strum, S L; Leone, P A et al. (1992) The neutrophil respiratory burst mechanism. Immunol Ser 57:47-76 |
