The major objective of this research proposal is to establish the involvement of diffusible, cytotoxic products of peroxidation in hyperopia-induced lung injury. The diffusible cytotoxins to be examined in mammalian systems in vitro and in vivo include toxic lipid aldehydes (4-hydroxyalkenals such as 4-2hydroxynonenal), toxic lipid hydroperoxides, and H202. These substances were selected for study on the basis of 1) direct evidence in the literature that peroxidation is accompanied by the formation of these toxins, and 2) known toxic effects of these diffusible cytotoxins are very similar to the observed in vivo toxicities with hyperoxic exposure. The initial focus of this research will be to characterize the contribution of these cytotoxic substances to the lung injury process initiated by hyperopia utilizing in vivo (newborn rabbit) as well as in vitro systems (selected lung cells in culture and H202-resistant cells). The degree of oxygen-induced injury (or protection from injury) in the lung as well as in cell culture systems will be assayed by quantitative assessment of selected morphologic, biochemical, physiological, and survival parameters. Differential lung cell sensitivity to O2-induced injury will be correlated with the production of and/or susceptibility to diffusible cytotoxins. The effects of clinically significant nutritional modifications, pharmacologic agents, and antioxidant enzymes on the production of and the susceptibility of different cell types to these cytotoxins will also be investigated. The goal of this research is to identify therapeutic protocols that will provide protection from hyperoxia-induced lung damage in prematurely born infants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL042057-02
Application #
3360034
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1988-12-01
Project End
1992-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kinter, M; Wolstenholme, J T; Thornhill, B A et al. (1999) Unilateral ureteral obstruction impairs renal antioxidant enzyme activation during sodium depletion. Kidney Int 55:1327-34
Brown, K E; Kinter, M T; Oberley, T D et al. (1998) Enhanced gamma-glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload. Free Radic Biol Med 24:545-55
Kinter, M; Roberts, R J (1996) Glutathione consumption and glutathione peroxidase inactivation in fibroblast cell lines by 4-hydroxy-2-nonenal. Free Radic Biol Med 21:457-62
Kinter, M; Spitz, D R; Roberts, R J (1996) Oleic acid incorporation protects cultured hamster fibroblasts from oxygen-induced cytotoxicity. J Nutr 126:2952-9
Grace, J M; MacDonald, T L; Roberts, R J et al. (1996) Determination of site-specific modifications of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal using matrix assisted laser desorption time-of-flight mass spectrometry. Free Radic Res 25:23-9
Spitz, D R; Kinter, M T; Roberts, R J (1995) Contribution of increased glutathione content to mechanisms of oxidative stress resistance in hydrogen peroxide resistant hamster fibroblasts. J Cell Physiol 165:600-9
Walker, M W; Kinter, M T; Roberts, R J et al. (1995) Nitric oxide-induced cytotoxicity: involvement of cellular resistance to oxidative stress and the role of glutathione in protection. Pediatr Res 37:41-9
Kinter, M; Robinson, C S; Grimminger, L C et al. (1994) Whole blood and plasma concentrations of 4-hydroxy-2-nonenal in Watanabe heritable hyperlipidemic versus New Zealand White rabbits. Biochem Biophys Res Commun 199:671-5
Spitz, D R; Phillips, J W; Adams, D T et al. (1993) Cellular resistance to oxidative stress is accompanied by resistance to cisplatin: the significance of increased catalase activity and total glutathione in hydrogen peroxide-resistant fibroblasts. J Cell Physiol 156:72-9
Goligorsky, M S; Morgan, M A; Lyubsky, S et al. (1993) Establishment of a hydrogen peroxide resistant variant of renal tubular epithelial cells: role of calcium-independent phospholipase A2 in cell damage. Arch Biochem Biophys 301:119-28

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