Gert S. Maritz

Fetal growth restriction has long-term effects on postnatal lung structure in sheep.

We have previously shown that fetal growth restriction (FGR) during late gestation in sheep affects lung development in the near-term fetus and at 8 wk after birth. In the present study, our aim was to determine the effects of FGR on the structure of the lungs at 2 y after birth; our hypothesis was that changes observed at 8 wk after birth would persist until maturity. FGR was induced in sheep by umbilicoplacental embolization, which was maintained from 120 d until delivery at term (approximately 147 d); birth weights of FGR lambs were 41% lower than in controls. At 2 y after birth, body and lung weights were not different, but there were 28% fewer alveoli and alveoli were significantly larger than in controls; hence there was a 10% reduction in the internal surface area relative to lung volume in FGR sheep compared with controls. The lungs of FGR sheep, compared with controls, had thicker interalveolar septa as a result of increased extracellular matrix deposition; the alveolar blood–air barrier was also thicker, largely because of an 82% increase in basement membrane thickness. These changes are qualitatively similar to those observed at 8 wk. Our data show that structural alterations in the lungs induced by FGR that were apparent at 8 wk were still evident at 2 y after birth, indicating that FGR may result in permanent changes in the structure of the lungs of the offspring and may affect respiratory health and lung aging later in life.

Life-long Programming Implications of Exposure to Tobacco Smoking and Nicotine Before and Soon After Birth: Evidence for Altered Lung Development

Tobacco smoking during pregnancy remains common, especially in indigenous communities, and likely contributes to respiratory illness in exposed offspring. It is now well established that components of tobacco smoke, notably nicotine, can affect multiple organs in the fetus and newborn, potentially with life-long consequences. Recent studies have shown that nicotine can permanently affect the developing lung such that its final structure and function are adversely affected; these changes can increase the risk of respiratory illness and accelerate the decline in lung function with age. In this review we discuss the impact of maternal smoking on the lungs and consider the evidence that smoking can have life-long, programming consequences for exposed offspring. Exposure to maternal tobacco smoking and nicotine intake during pregnancy and lactation changes the genetic program that controls the development and aging of the lungs of the offspring. Changes in the conducting airways and alveoli reduce lung function in exposed offspring, rendering the lungs more susceptible to obstructive lung disease and accelerating lung aging. Although it is generally accepted that prevention of maternal smoking during pregnancy and lactation is essential, current knowledge of the effects of nicotine on lung development does not support the use of nicotine replacement therapy in this group.

Critical Review Nicotine for the Fetus, the Infant and the Adolescent?

The recent expansion of Nicotine Replacement Therapy to pregnant women and children ignores the fact that nicotine impairs, disrupts, duplicates and/or interacts with essential physiological functions and is involved in tobacco-related carcinogenesis. The main concerns in the present context are its fetotoxicity and neuroteratogenicity that can cause cognitive, affective and behavioral disorders in children born to mothers exposed to nicotine during pregnancy, and the detrimental effects of nicotine on the growing organism. Hence, the use of nicotine, whose efficacy in treating nicotine addiction is controversial even in adults, must be strictly avoided in pregnancy, breastfeeding, childhood and adolescence.

Maternal and fetal origins of lung disease in adulthood.

This review focuses on genetic and environmental influences that result in long term alterations in lung structure and function. Environmental factors operating during fetal and early postnatal life can have persistent effects on lung development and so influence lung function and respiratory health throughout life. Common factors affecting the quality of the intrauterine environment that can alter lung development include fetal nutrient and oxygen availability leading to intrauterine growth restriction, fetal intrathoracic space, intrauterine infection or inflammation, maternal tobacco smoking and other drug exposures. Similarly, factors that operate during early postnatal life, such as mechanical ventilation and high FiO(2) in the case of preterm birth, undernutrition, exposure to tobacco smoke and respiratory infections, can all lead to persistent alterations in lung structure and function. Greater awareness of the many prenatal and early postnatal factors that can alter lung development will help to improve lung development and hence respiratory health throughout life.

The compromised intra-uterine environment: Implications for future lung health

1. Epidemiological studies of infants, children and adults indicate that prenatal compromises that restrict fetal growth and cause low birthweight increase the risk of respiratory deficiencies after birth.

Repeated ethanol exposure during late gestation alters the maturation and innate immune status of the ovine fetal lung

Little is known about the effects of fetal ethanol exposure on lung development. Our aim was to determine the effects of repeated ethanol exposure during late gestation on fetal lung growth, maturation, and inflammatory status. Pregnant ewes were chronically catheterized at 91 days of gestational age (DGA; term approximately 147 days). From 95-133 DGA, ewes were given a 1-h daily infusion of either 0.75 g ethanol/kg (n = 9) or saline (n = 8), with tissue collection at 134 DGA. Fetal lungs were examined for changes in tissue growth, structure, maturation, inflammation, and oxidative stress. Between treatment groups, there were no differences in lung weight, DNA and protein contents, percent proliferating and apoptotic cells, tissue and air-space fractions, alveolar number and mean linear intercept, septal thickness, type-II cell number and elastin content. Ethanol exposure caused a 75% increase in pulmonary collagen I alpha1 mRNA levels (P < 0.05) and a significant increase in collagen deposition. Surfactant protein (SP)-A and SP-B mRNA levels were approximately one third of control levels following ethanol exposure (P < 0.05). The mRNA levels of the proinflammatory cytokines interleukin (IL)-1beta and IL-8 were also lower (P < 0.05) in ethanol-exposed fetuses compared with controls. Pulmonary malondialdehyde levels tended to be increased (P = 0.07) in ethanol-exposed fetuses. Daily exposure of the fetus to ethanol during the last third of gestation alters extracellular matrix deposition and surfactant protein gene expression, which could increase the risk of respiratory distress syndrome after birth. Changes to the innate immune status of the fetus could increase the susceptibility of the neonatal lungs to infection.

MATERNAL NICOTINE EXPOSURE DURING GESTATION AND LACTATION OF RATS INDUCE MICROSCOPIC EMPHYSEMA IN THE OFFSPRING

The aim of this study was thus to determine whether maternal nicotine exposure during gestation and lactation will result in early emphysema in the lungs of the offspring. Female rats received nicotine subcutaneously during gestation and lactation. Nicotine administration commenced 1 day after mating and lasted until weaning on postnatal day 21. The offspring were exposed to nicotine via the placenta and mothers milk only. Lung tissue of the neonates was collected for analysis on postnatal days 14, 21, 35 and 42. The results show that maternal nicotine exposure had no effect on the total alveolar count (Na), mean alveolar volume (Valv), and airspace wall surface area per unit volume of lung tissue (AWUV) of the 14- and 21-day-old rat pups. However, the Na of the 35- and 42-day-old control animals was higher than that of the nicotine exposed animals. The Valv of the 35- and 42-day-old nicotine exposed rat pups was however larger than that of the control animals, whereas the AWUV of the 35- and 42-day-old control animals were bigger than that of the nicotine-exposed animals of the same age. The scanning electron micrographs showed a gradual flattening of the alveoli. It is therefore concluded that maternal nicotine exposure induced changes at gene level that renders the lungs of the offspring more susceptible to emphysema-like lesions.

Effects of intra-uterine growth restriction on the control of breathing and lung development after birth.

1. Low birthweight is now recognized as an important risk factor for early postnatal respiratory illness and it is becoming evident that low birthweight can increase the risk for airway dysfunction in children and adults. Our studies have been aimed at determining how low birthweight, resulting from intra‐uterine growth restriction (IUGR), affects the control of breathing and the structural and functional development of the lung.

Effect of Maternal Nicotine Exposure on Growth in vivo of Lung Tissue of Neonatal Rats

The effect of maternal nicotine exposure on lung growth in vivo in neonatal rats was investigated. Nicotine (0.25 and 1.0 mg/kg/day) administered subcutaneously to the pregnant animal from day 7 of gestation until weaning resulted in smaller neonatal lungs that were about 15% smaller on postnatal day 8. On day 21 no difference in lung mass occurs. Maternal nicotine exposure also causes enhanced lung cellular multiplication as judged by the calculated daily increase in DNA of 0.19 mg/g for control lung and 0.31 mg/g for experimental lung. Comparison of the protein/DNA ratio 5.75 +/- 0.22 of the control and the 3.59 +/- 0.21 of nicotine-exposed lungs showed that the cells of the latter was smaller. The lower lung mass was attributed to the smaller cell size. It is proposed that nicotines marked inhibitory (42%) effect on glycolysis probably results in type I cell injury and consequently enhanced cell proliferation.

Maternal Nicotine Exposure and Carbohydrate Metabolism of Fetal and Neonatal Lung Tissue: Response to Nicotine Withdrawal

The metabolic response of fetal and neonatal lung tissue to maternal nicotine exposure (0.25 and 1.0 mg/kg body weight/day) was investigated. White virgin female rats (Wistar) of 200-250 g were used. The rats were mated overnight and were afterwards randomly assigned to control and experimental groups. The experimental group was subdivided into two groups. One group received nicotine during pregnancy and lactation. The second group received nicotine only during lactation. The suckling rats were killed 24 h after the last dose of nicotine was administered to the mother. The lung tissue was surgically removed and the in vitro utilization of exogenous glucose and endogenous glycogen determined. Lactate production was also determined to assess glycolytic activity. Maternal nicotine administration during pregnancy and lactation stimulated total glucose turnover by 21.6 and 86.4% respectively but suppressed glycogenolysis (32.7%) and glycolysis by 24.6% (p less than 0.01). Nicotine administration during lactation only enhanced total glucose turnover by 19.1% (p less than 0.01) and glycogenolysis by 30% (p less than 0.01) but inhibited glycolysis by 25.8%. After 4 weeks of nicotine withdrawal when the rats were 7 weeks old, glycogenolysis and glycolysis of those animals exposed to nicotine via the placenta and mothers milk were still inhibited to the same extent as during exposure. Glycogenolysis and the glycolytic flux of lung tissue of rats exposed to nicotine via mothers milk only returned to normal.(ABSTRACT TRUNCATED AT 250 WORDS)