Superoxide production by cell surface NADPH oxidase is a central mechanism for neutrophil microbicidal activity and regulation of local inflammation. However, considerable animal and human evidence implicates neutrophil-derived superoxide in the pathogenesis of the adult respiratory distress syndrome (ARDS) commonly afflicting burn and trauma patients, and associated with a high mortality. The long-term goals of this project are to develop methods for utilizing regulatory processes to limit superoxide production and lung injury. Superoxide production is initiated by binding of a ligand to its specific cell surface receptor, which induces translocation of components of the NADPH oxidase from secondary granules. The process of translocation is regulated by a variety of mechanisms operating at both the granular and receptor level. These include receptor number, affinity, and rate of recycling of receptors following internalization, and adenylic cyclase location and activity. A specific role for cAMP has not been defined, but current evidence supports a regulatory role in translocation. We will characterize alterations in superoxide production occurring in patients at risk of ARDS, and examine the function of regulatory mechanisms affecting translocation and oxidase expression. Activity of FMLP receptors on patient cells, determined by H3-FMLP Scatchard analyses, will be correlated with superoxide production. The role of adenylic cyclase activity will be examined utilizing time-course studies of cAMP production in patient cells and in normal cells pretreated with the putative adenylic cyclase activator adenosine. Translocation of receptors and cyclase will be examined using cell fractionation techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031754-07
Application #
3280047
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1983-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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