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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Cincinnati
Schools of Medicine
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Burnett, R J; Lyden, C A; Tindal, C J et al. (1996) Mononuclear cell line THP-1 internalizes bactericidal/permeability-increasing protein by a non-receptor-mediated mechanism consistent with pinocytosis. Arch Surg 131:200-5;discussion 206
Solomkin, J S; Bass, R C; Bjornson, H S et al. (1994) Alterations of neutrophil responses to tumor necrosis factor alpha and interleukin-8 following human endotoxemia. Infect Immun 62:943-7
Tennenberg, S D; Clardy, C W; Bailey, W W et al. (1990) Complement activation and lung permeability during cardiopulmonary bypass. Ann Thorac Surg 50:597-601
Tennenberg, S D; Solomkin, J S (1990) Activation of neutrophils by cachectin/tumor necrosis factor: priming of N-formyl-methionyl-leucyl-phenylalanine-induced oxidative responsiveness via receptor mobilization without degranulation. J Leukoc Biol 47:217-23
Tennenberg, S D; Zemlan, F P; Solomkin, J S (1988) Characterization of N-formyl-methionyl-leucyl-phenylalanine receptors on human neutrophils. Effects of isolation and temperature on receptor expression and functional activity. J Immunol 141:3937-44
Tennenberg, S D; Solomkin, J S (1988) Neutrophil activation in sepsis. The relationship between fmet-leu-phe receptor mobilization and oxidative activity. Arch Surg 123:171-5
Tennenberg, S D; Jacobs, M P; Solomkin, J S (1987) Complement-mediated neutrophil activation in sepsis- and trauma-related adult respiratory distress syndrome. Clarification with radioaerosol lung scans. Arch Surg 122:26-32
Tennenberg, S D; Jacobs, M P; Solomkin, J S et al. (1987) Increased pulmonary alveolar-capillary permeability in patients at risk for adult respiratory distress syndrome. Crit Care Med 15:289-93
Tennenberg, S D; Solomkin, J S (1987) Surface receptor mobilization in complement-mediated neutrophil activation: characterization and effects of methylprednisolone. J Surg Res 43:143-8
Tennenberg, S D; Bailey, W W; Cotta, L A et al. (1986) The effects of methylprednisolone on complement-mediated neutrophil activation during cardiopulmonary bypass. Surgery 100:134-42