Lung Development in the Streptozotocin Rat Fetus: Antioxidant Enzymes and Survival in High Oxygen

Abstract

ABSTRACT. Offspring of experimentally induced diabetic DSPC, disaturated phosphatidylcholine animals demonstrate delays in functional, biochemical, and Lm, mean linear intercept morphological aspects of lung maturation, dealing mainly with the surfactant system. To investigate whether the development of the lung antioxidant enzyme system would be similarly delayed, and thus compromise their tolerance to high O2 exposure, we did the following: 1) produced the diabetic state in rats with streptozotocin injection 24 h after the onset of pregnancy; 2) examined fetal animals from streptozotocin and control rats at gestational days 19, 20, and 21, and newborn animals at day 22 for whole lung disaturated phosphatidylcholine and total phospholipid and for the three antioxidant enzymes: superoxide dismutase, catalase, glutathione peroxidase; and 3) exposed newborn offspring from steptozotocin-treated and control rats to >95% O2 for several days and their survival, changes in antioxidant enzymes and disaturated phosphatidylcholine and light microscopic findings in response to hyperoxic challenge were compared. Streptozotocin offspring demonstrated essentially no developmental differences in whole lung disaturated phosphatidylcholine, total phospholipid, or antioxidant enzymes activity at the 4 gestational days studied. However, newborns of streptozotocin mothers had consistently superior tolerance to hyperoxic exposure, consisting of increased survival 123134 (68%) versus 8/26 (31%) in controls, after 02-exposure for 13 days, p < 0.0011, microscopic evidence of reduced inhibition of alveolarization (p < 0.05), and a trend toward greater antioxidant enzymes response. Thus, in this animal model of experimental diabetes, neither the development of the antioxidant enzymes system nor the development of the surfactant system (as assessed by whole lung disaturated phosphatidylcholine and total phospholipid) appear delayed. However, the superior tolerance to hyperoxic exposure in streptozotocin offspring raises the question whether maternal diabetes might actually have a protective influence against 02-induced lung damage in prematurely delivered infants of diabetic mothers. IDM have a 6-fold increased risk of developing HMD compared to infants whose mothers are not diabetic (1). This increase in HMD has been attributed to a delay in lung maturation in the IDM. Numerous animal studies both in vivo and in vitro have reported delays in functional, biochemical, and morphological lung development in the IDM, focusing mainly on the surfactant system and the differentiation of the type I1 epithelial cell (2-7). Those infants of diabetic mothers who develop HMD usually require treatment with increased concentrations of inspired oxygen. The antioxidant enzyme system of the lung, consisting in part of superoxide dismutase, catalase, and glutathione peroxidase, is an important defense against free radicals and other toxic O2 metabolites produced intracellularly in excess amounts during exposure to hyperoxia. The development of the pulmonar...

Delay in rat lung alveolarization after the combined exposure of maternal hyperglycemia and postnatal hyperoxia

“…Therefore, we supposed that hyperglycemia‐primed lungs would be deficient of anti‐oxidative defence and more susceptible to hyperoxia‐related injury. In line with a previous study with a similar animal model, however, we did not find any remarkable changes in the measured markers of lung oxidative stress …”

“…In the present study, hyperglycemia priming preserved alveolar size as alveolar chord length in 7‐day‐old DM/O2 pups resembled to those without any exposure, indicating that the primary septa formation may not been affected. This is in accordance with a previous study in which rat pups of STZ‐induced diabetic dams manifested tolerance against hyperoxic challenge shown as significantly smaller increase in mean airspace size compared to hyperoxia‐exposed pups . Together with increased survival in their study, the authors even speculated whether maternal diabetes might actually have a protective influence against O 2 ‐induced lung damage …”

“…The detrimental effect of supplemental oxygen in the pathophysiology of bronchopulmonary dysplasia has been extensively reviewed both clinically and experimentally . Little information, however, exists on the possible priming effect of fetal hyperglycemic exposure on postnatal lung injury, although increased oxygen tolerance has been reported in neonatal rat lungs of hyperglycemic dams . In this study, we examined the combined effect of postnatal oxygen exposure in hyperglycemia‐primed neonatal rat lungs on lung morphology and the possible concomitant changes in pulmonary cell apoptosis and proliferation.…”

Cytotoxic factor in the serum of diabetic rats and its increase during pregnancy

“…However, removal of IGF-binding proteins from diabetic preg¬ nant rat serum did not cause an increase in thymidine incorporation by fetal lung cells (Table 5). DISCUSSION There exists both clinical (Robert et al 1976;Drew et al 1978) and experimental (Mintz, Chez & Hutch¬ inson, 1972;Mulay &McNaughton, 1983;Sosenko& Frank, 1986;Eriksson, Thunberg & Eriksson, 1989) evidence that maternal diabetes results in develop¬ mental abnormalities of the fetus but the underlying mechanisms are not fully understood (Bourbon & Farrell, 1985). Although fetal hyperglycaemia and hyperinsulinaemia encountered during diabetic pregnancy (Aerts & Van Assche, 1977;Mulay & McNaughton, 1983;Gewolb et al 1985;Eriksson, 1988) have been implicated as caus¬ ative factors (Pedersen, 1977), a consistent rela¬ tionship between these and developmental abnormalities is lacking.…”

My Personal Tribute to Dr. Mary Ellen Avery

“…I remember her delight when I presented my findings at research meetings and had my first peer-reviewed publications in the New England Journal of Medicine (2) and Journal of Applied Physiology (3). In fact, when I moved on to University of Miami, I continued the line of research looking at lung development in the animal model of the IDM, this time examining pulmonary antioxidant enzyme development in offspring of streptozotocin-treated rats (8). …”