We hypothesized that a possible mechanism to explain the significant increases that occur in the pulmonary antioxidant enzyme (AOE) system late in gestation might be an endogenous increase in the normal reactive O2 substrates for these enzymes. We found that lung O2 free radical formation increased -175% between fetal day 18 and birth (p < 0.01). We also found that late fetal rat lung mitochondrial and microsomal rates of AOE substrate (H2O2) generation increased markedly, and there was also significantly increased lung lipid peroxidation products with increasing gestational age. These definite elevations in reactive O2 species production in parallel with the time course of maturational elevations in the pulmonary AOE system, suggest that increasing enzyme substrate concentrations could be a primary controlling mechanism for increasing lung AOE gene expression in preparation for birth of the newborn.
Premature rabbits, unlike full-term rabbits, are unable to mount a protective increase in pulmonary antioxidant enzyme (AOE) activities in response to 48 h of hyperoxic exposure and demonstrate increased pulmonary 0, toxicity compared with full-term rabbits. To examine AOE gene expression of CuZn superoxide dismutase (SOD), Mn SOD, catalase, and glutathione peroxidase in preterm versus tcrm rabbits in response to hyperoxia, 29.5 d preterm rabbits (delivered by hysterotomy) and term rabbits (spontaneously vaginally delivered) were exposed to 48 h of >90% O2 or room air. Preterm rabbits had a significant increase in CuZn SOD rnRNA without corresponding AOE activity increases, suggesting translational1posttranslational inhibition. In full-term rabbits, the magnitude of lung AOE mRNA changes was associated with concordant magnitude changes in activities of CuZn SOD, Mn SOD, and catalase, suggesting pretranslational regulation of AOE gene expression; glutathione peroxidase, however, appears to be regulated translationally1 posttranslationally. To investigate potential pharmacologic means of overcoming the susceptibility of the preterm rabbit to 0, toxicity, 29.5 d preterm rabbits received 20-40 kgikg of Salmonella typhimurium endotoxin or diluent S.C. (after birth and at 24 h); in separate experiments, pregnant rabbits received intramuscular injections of dexarnethasone (0.01-0.05 mgikg) orThe incidence of chronic lung disease in human premature infants increases with decreasing gestational age (1) and is thought to be related in part to oxygen free radical-induced lung injury. In an attempt to explain the mechanisms involved with this chronic lung process and these epidemiologic observations, we have previously demonstrated that premature rabbits have decreased baseline activity levels of pulmonary AOE (2) and are also unable to mount a protective increase in AOE saline on gestational d 27.5 and 28.5 and undcrwent hysterotomy at 29.5 d. After hyperoxic exposurc, postnatal endotoxin trcatment of pretcrm rabbits resulted in significant increascs in CuZn SOD activity and CuZn SOD mRNA, suggesting a rcvcrsal of the translational/posttranslational inhibition characlcristic of the pretcrm rabbit, improved hyperoxic survival (74181 = 91% venc.~ls 70192 = 76%, p < 0.05; endotoxin versus controls), and protcction against hyperoxia-induced increases in lung lavage protein (+4% endotoxin versus +28% controls, 11 < 0.05). Prenatal dexamethasone neither improved hypcroxic survival, protcctcd against 0, toxicity, nor produced increases in any of the AOE aftcr 48 h of hyperoxia relative to air-breathing preterm rabbits. activities in response to 48-72 h of hyperoxic cxposure (3). Conversely, full-term newborn rabbits are able to significantly increase AOE activities with hyperoxia (3). Compared with term rabbits, which demonstrate minimal evidencc of hyperoxic lung damage, preterm rabbits manifest increases in sevcral indices of pulmonary 0, toxicity, including lung lavage fluid protein content, lung conjugated diene levels, and l...
IIBSTRIICr. Epidermal growth factor (EGF) has been shown to accelerate fetal lung maturation in rabbits, lambs, and rhesus monkeys in riro and increase surfactant synthesis in vitro. Its effect on the maturation of the lung antioxidant enzyme system, however, is unknown. We studied the effect of EGF (10 nhl) on 19-d fetal rat lung esplant cultures in serum-free medium in air/S% C 0 2 or >90% 0 2 / 5 % C 0 2 compared with similarly grown control cultures in air or hyperosia a t 72 h. Fetal lung activities of superoxide dismutase and catalase were unchanged by EGF in air, whereas glutathione peroxidase activity was significantly decreased ( p < 0.05 rersus air control). lIowever, in hyperosia, EGF-treated fetal lung cultures had significantly elevated superoside dismutase and catalase activities ( p < 0.01) versus 02-exposed controls, and glutathione perosidase activity similar to that of controls. 'l'he mRNA levels for all the antioxidant enzymes showed patterns similar to the enzyme activities escept in the case of Cu,Znsuperoside dismutase mKNA, which increased in EGF-air cultures. E G F decreased the rate of '11-choline incorporation into disaturated phosphatidylcholine in air (p < 0.01 versus air control), but increased disaturated phosphatidylcholine synthesis in response to hyperosia ( p < 0.01 rersus O 2 control). The histologic appearance of EGF-treated cultures in O2 was superior to that of 02-exposed controls, which showed thickened septa1 walls, decreased surfactant in the air spaces, and epithelial cell mitochondria1 swelling. EGF therefore accelerates antiosidant enzyme and disaturated phosphatidylcholine maturation under hyperosic conditions and protects fetal rat lung cultures from hyperosic injury. This accelerated 02-dependent maturation by EGF occurs at the pretranslational level. TNA, total nucleic acidIn all mammalian species studied to date, there is a late gestational increase in surfactant and a par;1IIeI increase in the AOE system ofthe lungs ( I , 2). These late gestational biochemical changes prepare the fctal lungs for the transition from a fluidfilled state in a relatively 0.-poor intrauterine environment to air breathing in a relatively 0.-rich environment at birth (3). The prematurely born infant with a poorly developed surfactant system is prone to develop severe RDS and requires early mechanical ventilation combined with 0. therapy. Prolonged 0. therapy is associated with the development of chronic lung disease or bronchopulmonary dysplasia believed to be due in part to a poorly developed AOE defense system to counteract toxic O2 radical species generated by hyperoxia (3. 4).Lung maturation is known to be regulated or modulated by a number of hormones, among them the polypeptide EGF (5). 111 viro, EGF has been shown to enhance maturation of alveolar type 11 cells and increase surfactant production in fetal rabbits (6, 7) and rhcsus monkeys (8). Similarly. E G F increased morphologic maturation of the fetal lung and decreased RDS in fetal lambs (9). EGF also caused similar effects ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.