Oxygen toxicity may cause deleterious effects in the lung and may account for some of the changes of chronic lung disease of the newborn. The inducible isoenzyme of heme oxygenase (HO-1) is known to be upregulated in hyperoxia. Furthermore, moderate levels of HO-1 expression are associated with increased protection against oxygen toxicity in vitro. However, the effect of higher HO-1 expression has not been examined clearly and preliminary studies suggest an optimal range of HO-1 over-expression in antioxidant defenses in vitro. Nothing is known about the effect of over-expression or elimination of HO-2, the constitutive isoenzyme in vitro, but recent observations suggest that HO-2, unlike HO-1, may additionally serve to sequester heme at two binding sites thereby suggesting that the two isoenzymes serve in differing roles in oxygen toxicity. As to the in vivo role of both HO isoenzymes, it has recently been shown that absence of HO is detrimental to adult mutant mice. Aging null mutants lacking HO-1 had increased markers of oxidative injury and younger HO-2 null mutants had increased susceptibility to oxygen toxicity. Since it is known that both HO-1 and H0-2 are expressed at higher levels in the lungs of newly born animals compared to adults, we speculate that HO is even more relevant to neonatal antioxidant defense in vivo. In this proposal, in order to further define the role of HO in antioxidant defense, we plan to precisely modulate HO expression in cultured fetal pulmonary cells using a tetracycline regulated promoter to define whether there is an optimal range HO expression in vitro. We will also use neonatal mutant mice that lack HO-1 or HO-2 and transgenic mice which over-express HO-1 or HO-2 to determine if HO expression is associated with protection against hyperoxia in vivo. Lastly, we will determine whether differences exist in the antioxidant function of HO-1 and HO-2 in vitro and in vivo. Prior to considering modulation of HO as a therapeutic intervention, it will be necessary to clarify whether HO is protective against hyperoxic injury in vivo and to understand what manner and magnitude of HO expression is most beneficial to cells. A better understanding of the role of lung HO in the neonate will allow us to identify strategies to enhance this endogenous neonatal antioxidant defense.
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