I plan to investigate both endogenous and exogenous means of protecting the lung from the toxic changes associated with prolonged exposures to high concentrations of 02, and from several other agents which are believed to cause lung damage by very similar biochemical (oxidant) mechanisms (including paraquat, bleomycin and lung irradiation). I wish to continue to study the role of the endogenous peroxidase system -- in protecting the lung from the highly reactive 02 free-radicals produced by hyperoxia and these other oxidant agents. The ability to respond to hyperoxidant challenge with increased antioxidant enzyme activity has been shown by us to be a characteristic response in 02-tolerant newborn animals, but a response that is lacking in 02-susceptible adult animals. The reason for this disparity in sensitivity to 02-induced lung damage and lethality will be a major area to be examined. I especially wish to learn more about the mechanism of action of bacterial endotoxin, which I have found provides more marked protection against experimental 02 toxicity than any other exogenous agent reported to date (Survival of adult rats in hyperoxia increased from approximately 25% (untreated) to greater than 95% with endotoxin treatment). I also wish to test the effectiveness of endotoxin (and """"""""endotoxoids"""""""" - chemically detoxified endotoxin) in protecting the lung from the damage produced by the other oxidant agents mentioned above. Finally, I wish to follow up on our recent finding that the antioxidant enzymes show significant increases in activity in fetal rabbit lungs just prior to the end of gestation and birth. This may have important implications for the susceptibility of the prematurely-born (human infant) to early clinical hyperoxic treatment. Studies are planned to determine what controls the late fetal rise in these protective lung enzymes (hormonal?) and whether their activity can be prematurely stimulated in the lung in utero.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001230-04
Application #
3073695
Study Section
Pathology A Study Section (PTHA)
Project Start
1983-12-01
Project End
1988-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33101
Sosenko, I R; Frank, L (1989) Thyroid inhibition and developmental increases in fetal rat lung antioxidant enzymes. Am J Physiol 257:L94-9
Sosenko, I R; Nielsen, H C; Frank, L (1989) Lack of sex differences in antioxidant enzyme development in the fetal rabbit lung. Pediatr Res 26:16-9
Hass, M A; Iqbal, J; Clerch, L B et al. (1989) Rat lung Cu,Zn superoxide dismutase. Isolation and sequence of a full-length cDNA and studies of enzyme induction. J Clin Invest 83:1241-6
Frank, L; Iqbal, J; Hass, M et al. (1989) New ""rest period"" protocol for inducing tolerance to high O2 exposure in adult rats. Am J Physiol 257:L226-31
Sosenko, I R; Innis, S M; Frank, L (1989) Menhaden fish oil, n-3 polyunsaturated fatty acids, and protection of newborn rats from oxygen toxicity. Pediatr Res 25:399-404
Frank, L (1988) Extension of oxygen tolerance by treatment with endotoxin: means to improve its potential therapeutic safety in man. Exp Lung Res 14 Suppl:987-1003
Sosenko, I R; Innis, S M; Frank, L (1988) Polyunsaturated fatty acids and protection of newborn rats from oxygen toxicity. J Pediatr 112:630-7
Frank, L; Sosenko, I R (1988) Undernutrition as a major contributing factor in the pathogenesis of bronchopulmonary dysplasia. Am Rev Respir Dis 138:725-9
Sosenko, I R; Frank, L (1987) Thyroid hormone depresses antioxidant enzyme maturation in fetal rat lung. Am J Physiol 253:R592-8
Frank, L (1987) Oxygen toxicity in neonatal rats: the effect of endotoxin treatment on survival during and post-O2 exposure. Pediatr Res 21:109-15

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