Failure of Premature Rabbits to Increase Lung Antioxidant Enzyme Activities after Hyperoxic Exposure: Antioxidant Enzyme Gene Expression and Pharmacologic Intervention with Endotoxin and Dexamethasone

Abstract

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...

Inflammatory Mediators in the Immunobiology of Bronchopulmonary Dysplasia

“…The premature rabbits also had increased oxygen toxicity lung injury. In these experiments, the premature rabbit had a significant increase in CuZn SOD mRNA but without corresponding increase in AOE activity, suggesting translational/posttranslational inhibition [168]. In ventilated premature lambs, exposure to 100% oxygen for 24 h compared to PRN oxygen exposed actually resulted in a decrease in lung homogenate SOD, catalase, and glutathione peroxidase activity.…”

Altered Expression of Cyclins and Cdks in Premature Infant Baboon Model of Bronchopulmonary Dysplasia

“…Animals of 140-day gestation were given either continuous 100% oxygen or an inspired oxygen tension as needed [pro re nata (PRN)] to maintain paO 2 at 40-50 torr. Within 10 days, those 140-day animals given 100% oxygen develop lung histopathologic lesions that closely resemble human BPD, whereas the PRN animals do not develop these lesions, allowing near-normal lung development (16,28). More premature animals of 125-day gestation received immediate resuscitation with artificial surfactant, positive pressure ventilation, and PRN oxygen.…”

Increased Apoptosis and Expression of p21 and p53 in Premature Infant Baboon Model of Bronchopulmonary Dysplasia

“…Animals of 140-day gestation were given either continuous 100% oxygen or an inspired oxygen tension as needed [pro re nata (PRN)] to maintain paO 2 at 40-50 Torr. Within 10 days, those 140-day animals given 100% oxygen develop lung histopathologic lesions that closely resemble human BPD, whereas the PRN animals do not develop these lesions, allowing near-normal lung development (17,34). Most premature animals of 125-day gestation received immediate resuscitation with artificial surfactant, positive pressure ventilation, and PRN oxygen.…”

“…Most premature animals of 125-day gestation received immediate resuscitation with artificial surfactant, positive pressure ventilation, and PRN oxygen. These animals also develop BPD despite receiving lesser (PRN) inspired concentrations of oxygen (34). In either case, all animals received state-of-the-art care in a neonatal intensive care unit for up to 17 days.…”