Antioxidant Enzyme Development Research Articles

My Personal Tribute to Dr. Mary Ellen Avery

Because my husband was planning to pursue a fellowship in adolescent medicine at Boston Children’s Hospital, I was set to interview there in July of 1974 for a third year of pediatric training. I was just starting my second year of pediatrics in Los Angeles and had been focusing more on the mechanics of completing pediatric training than on choosing a fellowship. Dr. Mary Ellen Avery had just become Children’s Physician-in-Chief. In fact, she was still finding her way about the place, both physically and professionally. It was my second interview, the first resulting in less than positive news about the possibility of my obtaining a senior pediatric residency for the coming year. She did not let me be discouraged, made it known that she would welcome me there, and suggested I could pursue the start of a fellowship before completing my full pediatric training. What type of fellowship? I certainly hadn’t spent much time contemplating this. How about neonatology, she suggested, and immediately arranged for me to see Dr. Bill Taeusch, newly appointed Neonatology Division Director. So serendipity, and more importantly, Dr. Mel Avery are responsible for my career in neonatology: I joined the first official JPN fellows’ group that started training in July of 1975. Dr. Avery was a pioneering researcher in the field of neonatology and a great research motivator as well. She had overseen a recent publication associating an increased risk of hyaline membrane disease in infants of diabetic mothers (1). She “shepherded” me into examining this further, thus leading me both to the delivery room to collect infants’ cord blood for C-peptide measurements (2) and into the animal lab with alloxan-diabetic pregnant rabbits and the lung development of their offspring (3–7). 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). She opened her heart to me not just professionally but socially and personally as well. I remember a cozy Thanksgiving evening when just she, my husband, and I sat by the fire in her Wellesley condo and dined on delicious leftovers from the day. She hosted the two of us to a very special Boston evening: a “double date” with Dr. Fred Rosen for dinner at the Harvard Club and then to hear the Boston Symphony. When I was about to have my first child, she was glowing when I came to her with the news. She wanted to make sure I would be nursing him which of course I was. When he was born, she presented us with a beautifully framed print of a mother rabbit and her pups (how appropriate!) which we hung above his changing table. And once I had successfully established nursing and returned to work, she invited me to write an article with her on the benefits of breast feeding for the Harvard Medical School Health Letter (9). My respect and admiration for Dr. Mary Ellen Avery are without bounds. There is no doubt that Mel brought me into neonatology, fostered my career, and opened her intellect and heart to me many years ago. For this I am eternally grateful.

Effects of the glucocorticoid agonist, RU28362, and the antagonist RU486 on lung phosphatidylcholine and antioxidant enzyme development in the genetically obese zucker rat

The biochemical maturation of the lung in late gestation and in the young animal is regulated by glucocorticoids. The present study was aimed at dissociating the different glucocorticoid receptor sites involved in these regulatory functions. The obese Zucker rat was selected as a model for this study as it exhibits hypersensitivity to glucocorticoid hormone action by virtue of its elevated receptor numbers and activity. Two synthetic steroid analogues were administered to obese animals; RU28362, a specific type II receptor agonist, and the type II antagonist RU486. RU28362 promoted a strong catabolic effect, which was associated with reduced food intake and the abolition of growth in the rats. The agonist, RU28362, attenuated developmental increases in antioxidant enzyme activities, and altered the growth of the tissue. At the age studied, development of the lung phosphatidylcholine (PC) system was almost complete, but RU28362 increased disaturated PC 16:0/16:0 concentrations by almost 2-fold, and altered the molecular composition of total pulmonary PC. RU486 attenuated the growth of the rats and reduced their food intake. Treatment with the type II antagonist attenuated lung growth and increased the activities of pulmonary copper zinc (Cu/Zn) and manganese (Mn) superoxide dismutases. RU486 had no effect on lung PC concentrations and molecular composition. The data suggest a role for type I glucocorticoid receptors in the regulation of the antioxidant enzyme system in the lung, as type II antagonism will channel endogenous glucocorticoid binding to the type I site. Type II receptor binding would appear to play a role in regulating the lung PC content.

Development of antioxidant enzymes in rat brain and in reaggregation culture of fetal brain cells

The development of antioxidant enzymes in rat brain and reaggregation cultures of fetal brain cells was studied from embryonic day 15 to postnatal day 45. Both in vivo and in culture, the copper-zinc superoxide dismutase activity first increased and then decreased with age, whereas the manganese superoxide dismutase activity increased throughout the period. Catalase showed a maximum activity at day 5 after birth, thereafter decreasing to adult level around day 30, both in vivo and in culture. The glutathione peroxidase activity increased from the first week after birth and reached adult level at day 45. In culture, the activity of this enzyme was slightly lower. The good correlation between the development of the antioxidant enzymes in vivo and in culture suggests that reaggregation cultures might be a valuable system for studying defense mechanisms against free radicals in the brain.

Thyroid inhibition and developmental increases in fetal rat lung antioxidant enzymes.

After demonstrating that prenatal exogenous thyroid hormone administration to pregnant rats produces decreases in fetal lung antioxidant enzyme (AOE) development despite increases in surfactant development, we examined the role of endogenous thyroid hormones on the development of these two lung systems. We administered the antithyroid drug methimazole (or diluent) to pregnant rats for the final 3 days before premature or term delivery; in a second series of experiments, propylthiouracil was administered for the 10 days before delivery. Both antithyroid drugs, known to cross the placenta, produced significantly decreased thyroid hormone levels in the pregnant dams. Fetal offspring from methimazole-, and propylthiouracil-treated dams demonstrated significant increases in pulmonary superoxide dismutase activity at 20 and 21 days of gestation and in catalase and glutathione peroxidase activities at 21 days compared with control offspring. Surfactant, measured as lung tissue disaturated phosphatidylcholine, was not different between either experimental group and controls. These results suggest that thyroid blockade increases AOE because the influence of thyroid hormone on AOE development may be one of depression. The findings confirm that certain hormonal regulators may influence different developing fetal lung systems in different ways.

Lack of sex differences in antioxidant enzyme development in the fetal rabbit lung.

A sex difference characterized by a female advantage in the maturation of the fetal pulmonary surfactant system is well documented. Because the surfactant system and the antioxidant enzyme system of the fetal lung have chronologically similar developmental patterns and share some of the same hormonal regulators, such as glucocorticoids, we questioned whether a sex difference would be present in antioxidant enzyme maturation as it is in surfactant system maturation. We studied fetal rabbits at days 26 and 28 of a 31-day gestational period. Fetal sex was identified histologically. Fetal lung lavage was performed and lavage fluid assayed for phosphatidylcholine, disaturated phosphatidylcholine, and sphingomyelin. Lung tissue from separate fetuses was assayed for disaturated phosphatidylcholine content and total phospholipid content and for the activities of three antioxidant enzymes--superoxide dismutase, catalase, and glutathione peroxidase. No differences were present in antioxidant enzyme maturation between male and female fetal rabbits at the gestational days studied. A female advantage was observed in the lung lavage disaturated phosphatidylcholine/sphingomyelin ratio (at 26 days: female 1.38 +/- 0.42, male 0.99 +/- 0.26; and at 28 days: female 3.29 +/- 0.53; male 2.26 +/- 0.35, p less than 0.05). A female advantage in surfactant development was not reflected in lung tissue disaturated phosphatidylcholine or total phospholipid. We conclude that, unlike the development of the surfactant system, the development of the antioxidant enzyme system in the fetal rabbit lung does not demonstrate a sex difference.

Accelerated appearance of osmiophilic bodies in fetal lungs following steroid injection.

Accelerated appearance of osmiophilic bodies in fetal lungs following steroid injection.

Accelerated appearance of pulmonary surfactant in the fetal rabbit.

Accelerated appearance of pulmonary surfactant in the fetal rabbit.