Premature and sick newborns are often likely to receive high concentrations of oxygen and thus be at risk for oxidative stress due to hyperoxia. Oxidative injury may account for some of the changes seen in chronic lung disease (CLD) of the premature. In animals, preparation for birth and protection against oxidant stress involves the increase in antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase in the latter 10% to 15% of gestation. Premature infants may be compromised in their antioxidant capacity as they may not have the third trimester increase in the enzymes, as well as vitamins and cofactors that function as antioxidants. They could therefore be more at risk for the development of severe sequelae from oxygen toxicity. Heme oxygenase (HO), the rate limiting enzyme in the production of bilirubin has been shown to be elevated in neonatal animals. Recently, bilirubin has been identified as an antioxidant since it can prevent oxygen radical damage of fatty acids in vitro. Heme oxygenase itself may also participate in antioxidant defense by removing heme a potential generator of oxidative damage and inducing ferritin, which sequesters intracellular iron. HO activity and its induction may represent important transitional antioxidant defense mechanisms in the newborn since other antioxidant enzymes may be at low levels. We have demonstrated increases in activity, and protein content, of the inducible form of HO -HO-1 - in response to hyperoxia in neonates. We hypothesize that this response has evolved in the newborn to assist other antioxidant defenses. We propose to examine: 1) the role of HO-1 and HO-2 (the constitutive form of HO) in antioxidant defense in cell culture models with over- nd under-expression of this enzyme, and evaluate HO activity in oxygen and hydrogen peroxide (H2O2) resistant cells; 2) the ontogeny of HO in the lung to understand the normal pattern of development of HO in this organ, since this has not been described; 3) the mechanism of hyperoxic regulation of HO in neonatal animals by assessing changes in HO mRNA steady state levels, protein content and activity. We will evaluate pre- and postnatal HO-1 mRNA steady state levels, protein content and activity in rats and will look at localization of HO-1 mRNA and protein in the lung of rats and rabbits with in situ hybridization and immune histochemistry, respectively. These studies will help elucidate the role of HO in the hyperoxia and may give insight into the potential effects of present medical therapy on human neonatal antioxidant defense. Hopefully this will lead to strategies to enhance endogenous antioxidant defense in the newborn and prevent oxidative injury and its potential sequelae in developing organisms.
| Dennery, Phyllis A; Visner, Gary; Weng, Y i-Hao et al. (2003) Resistance to hyperoxia with heme oxygenase-1 disruption: role of iron. Free Radic Biol Med 34:124-33 |
| Dennery, Phyllis A; Lee, Christen S; Ford, Berendera S et al. (2003) Developmental expression of heme oxygenase in the rat lung. Pediatr Res 53:42-7 |
| Brown, Kyle E; Dennery, Phyllis A; Ridnour, Lisa A et al. (2003) Effect of iron overload and dietary fat on indices of oxidative stress and hepatic fibrogenesis in rats. Liver Int 23:232-42 |
| Yang, Guang; Shegog, Mychell L; Dennery, Phyllis A (2002) Effect of glutathione on lung activator protein-1 activation and heme oxygenase-1 induction in the immature rat. Pediatr Res 52:34-9 |
| Yang, G; Madan, A; Dennery, P A (2000) Maturational differences in hyperoxic AP-1 activation in rat lung. Am J Physiol Lung Cell Mol Physiol 278:L393-8 |
| Weng, Y H; Tatarov, A; Bartos, B P et al. (2000) HO-1 expression in type II pneumocytes after transpulmonary gene delivery. Am J Physiol Lung Cell Mol Physiol 278:L1273-9 |
| Mireles, L C; Lum, M A; Dennery, P A (1999) Antioxidant and cytotoxic effects of bilirubin on neonatal erythrocytes. Pediatr Res 45:355-62 |
| Dennery, P A; Spitz, D R; Yang, G et al. (1998) Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. J Clin Invest 101:1001-11 |
| Dennery, P A; Sridhar, K J; Lee, C S et al. (1997) Heme oxygenase-mediated resistance to oxygen toxicity in hamster fibroblasts. J Biol Chem 272:14937-42 |
| Dennery, P A; Wong, H E; Sridhar, K J et al. (1996) Differences in basal and hyperoxia-associated HO expression in oxidant-resistant hamster fibroblasts. Am J Physiol 271:L672-9 |
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