The interaction of platelets and leukocytes with vessel walls during injury repair and immune responses may create a local inflammatory condition in which active oxygen species are important components. The role of peroxides in this condition is incompletely understood, but they may modulate several inflammatory events. Peroxides at concentrations of 1 MuM in buffer are reported to impair endothelial cell function, but current data are insufficient to define the threshold for this damage by peroxide in the presence of proteins and enzymatic peroxide scavengers in biological systems. The limits for the involvement of peroxides in vascular injury also depend upon the levels of hydroperoxide in plasma during health and disease. To gain a more quantitative understanding of these limits, experiments are proposed to: determine the amount of lipid hydroperoxides in blood and the distribution of peroxide among various lipoprotein fractions; measure the response of vascular segments to hydroperoxides; and determine the ability of antiinflammatory agents to reduce blood hydroperoxides and to change vascular resistance to peroxide damage. To determine the concentrations of the peroxides in blood, a new, specific enzymatic assay will be used, and the results will be compared with those from the conventional thiobarbituric assay. Plasma lipoprotein fractions will be separated, and the peroxide concentration in each fraction will be measured. These measurements will be performed with plasma from healthy humans and patients with cardiovascular or immune-related diseases and from laboratory animals (rats, New Zealand White and Watanabe rabbits). The effect of different antioxidant and antiinflammatory agents upon the level of peroxides in plasma and on the susceptibility of the vascular tissues to the lipid peroxides will be examined. Changes in prostacyclin synthase, lactate dehydrogenase, and pyruvate kinase activities in vascular segments and subcellular fractions will be determined after challenge with different types of peroxides and different pharmacologic regimens. With the results of these experiments, the limits of the involvement of lipid hydroperoxides in vascular injury can be defined more precisely, and the need to pharmacologically modulate plasma levels of lipid hydroperoxides can be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL034422-01A1
Application #
3347300
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1986-04-01
Project End
1990-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Overall Medical
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Thelin, William R; Kesimer, Mehmet; Tarran, Robert et al. (2005) The cystic fibrosis transmembrane conductance regulator is regulated by a direct interaction with the protein phosphatase 2A. J Biol Chem 280:41512-20
Kulmacz, R J; Pendleton, R B; Lands, W E (1994) Interaction between peroxidase and cyclooxygenase activities in prostaglandin-endoperoxide synthase. Interpretation of reaction kinetics. J Biol Chem 269:5527-36
Keen, R R; Stella, L; Flanigan, D P et al. (1991) Differential detection of plasma hydroperoxides in sepsis. Crit Care Med 19:1114-9
Keen, R R; Stella, L A; Flanigan, D P et al. (1990) Differences between arterial and mixed venous levels of plasma hydroperoxides following major thoracic and abdominal operations. Free Radic Biol Med 9:485-94
Kulmacz, R J; Miller Jr, J F; Pendleton, R B et al. (1990) Cyclooxygenase initiation assay for hydroperoxides. Methods Enzymol 186:431-8
Rich, S; Miller Jr, J F; Charous, S et al. (1989) Development of atherosclerosis in genetically hyperlipidemic rabbits during chronic fish-oil ingestion. Arteriosclerosis 9:189-94
Pendleton, R B; Lands, W E (1987) Assay of lipid hydroperoxides by activation of cyclooxygenase activity. Free Radic Biol Med 3:337-9
Lands, W E (1987) Biochemical and cellular actions of membrane lipids. Am Rev Respir Dis 136:200-4