Role of Heme Oxygenase and Bilirubin in Oxidative Stress in Preterm Infants

Abstract

In a previous study, it was found that the decrease in the total plasma bilirubin level (Btot) in preterm infants was associated with the decrease in oxidative stress. We hypothesized that this occurs as a result of a pro-oxidant effect of heme oxygenase (HO), which outcompetes with the antioxidant properties of bilirubin. In this study we studied 12 preterm infants in whom the plasma levels of Btot, total hydroperoxide (TH), protein SH groups, HO activity, non-transferrin-bound iron (NTBI), and erythrocyte CuZn superoxide dismutase (CuZn SOD) activity were concurrently measured when the Btot was Ͼ220 M and after a Btot drop of Ͼ34 M. The Btot decrease was concurrent with the TH decrease, protein SH groups increase, and the HO and CuZn SOD activity increase and was not associated with an NTBI increase. We concluded that 1) Btot does not exert a meaningful antioxidant effect in vivo; 2) HO does not exert a pro-oxidant effect involving an NTBI increase and that, on the contrary, it could exert an antioxidant effect; and 3) the concurrent HO and CuZn SOD activity increase could indicate a synergic antioxidant effect of the two enzymes. Many illnesses in preterm infants, including chronic lung disease, necrotizing enterocolitis, retinopathy of prematurity, and intracranial hemorrhage, are thought to be related to the action of reactive oxygen species. This presumably occurs because the antioxidant system of preterm infants is at the same time highly stressed and incompletely developed (1). Moreover, it is well known that during the first days of life, the catabolism of fetal Hb results in a tissue burden of heme that is a potentially pro-oxidant damaging molecule that not only provides a lipophilic form of iron but can itself directly attack the lipid bilayer, the cytoskeleton, and DNA (2,3). Several reports have emphasized the antioxidant role of bilirubin, which in human neonatal plasma seems to have a greater antioxidant potency than urates, ␣-tocopherol, or ascorbates (4). Nevertheless, although the antioxidant effect of bilirubin as a scavenger of reactive oxygen species is well documented in vitro (5-8) as well as in animal studies (9), its role in vivo has not been definitively clarified in preterm infants (10 -13). Even less is known about the role of heme oxygenase (HO) in oxidative stress of the newborn infant. Heme oxygenase is the enzyme responsible for physiologic heme degradation into equimolar amounts of CO and biliverdin and the release of free iron (14). It has been suggested that its inducible form, HO-1, might represent a generalized response to oxidative stress (15)(16)(17) and that HO-1 could confer cellular protection against oxidant stress (14,18 -20). However, recent studies suggest that HO-1 induction might not always be beneficial and that the release of redox-active iron from heme might induce enhance oxidative stress (21,22).In a previous study, we found that in jaundiced preterm infants, a decrease of bilirubin plasma level (Btot) was asso-

Lack of the Antioxidant Glutathione Peroxidase-1 (GPx1) Exacerbates Retinopathy of Prematurity in Mice

“…34 In preterm infants, the expression of HO-1 is known to increase concurrently with a drop in total plasma bilirubin level and a reduction in total hydroperoxides, suggesting that HO-1 might play a role in reducing oxidative stress in premature infants. 35 Furthermore, HO-1 is thought to play an important role in retinal glial cells to protect photoreceptors from oxidative damage. 36,37 In this study, gene expression of HO-1 was increased in our model of ROP; however, the induction of HO-1 was not affected by the lack of GPx1.…”

Redox State, Oxidative Stress, and Molecular Mechanisms of Protective and Toxic Effects of Bilirubin on Cells

“…Further studies [68,69] found a substantially lower plasma oxidazibility in hyperbilirubinemic neonatal plasma than in normobilirubinemic adults. However, contradictory data have been reported [70,71].…”

Hyperbilirubinemia in preterm infants in Japan: New treatment criteria

“…Because the increased mortality observed in extremely preterm infants who are receiving PT and the injury to cell membranes and DNA by PT in in vitro studies suggest that it is prudent to use less intensive irradiance, it has been recommended to initiate PT at lower irradiance (standard PT), and to increase the level (intensive PT) only when TSB continues to rise . In addition, bilirubin is not only cytotoxic, it also has antioxidant effects for preterm infants, who are susceptible to oxidative stress …”