Influence of Intrauterine Growth Restriction on Airway Development in Fetal and Postnatal Sheep

Abstract

Epidemiologic studies suggest that intrauterine growth restriction (IUGR) can lead to impaired lung function, yet little information exists on the effects of IUGR on airway development. Our objectives were to characterize morphometrically effects of IUGR on airway structure in the fetus and to determine whether alterations persist into postnatal life. We used two groups of sheep, each with appropriate controls; a fetal group was subjected to IUGR by restriction of placental function from 120 to 140 d (term~147 d), and a postnatal group, killed 8 wk after birth, was subjected to IUGR from 120 d to birth at term. In both fetuses and postnatal lambs, IUGR did not alter lung weight relative to body weight. In IUGR fetuses, the luminal areas and basement membrane perimeters of the trachea and larger bronchi (generations 0 -8, trachea ϭ 0) were smaller than in controls. Airway wall areas, relative to basement membrane perimeters, were reduced in IUGR fetuses compared with controls, largely due to reduced areas of cartilage and epithelium. At 8 wk after birth, there were no significant differences in airway dimensions between IUGR and control lambs. However, the number of profiles of bronchial submucosal glands, relative to basement membrane perimeters, was lower in IUGR lambs than in controls and the area of epithelial mucin was increased. We conclude that restriction of fetal growth during late gestation impairs the growth of bronchial walls that could affect airway compliance in the immediate postnatal period. Although airway growth deficits are reversed by 8 wk, alterations in mucus elements persist. Abbreviations A adv , area within the adventitia A bm , area within the basement membrane A cart , area of cartilage layer A inep , area within the internal perimeter of the epithelium A ism , area within the inner perimeter of the smooth muscle layer A osm , area within the outer perimeter of the smooth muscle FEV 1 , forced expiratory volume in 1 s PaO 2 , partial pressure of arterial oxygen PaCO 2 , partial pressure of arterial carbon dioxide pHa, pH of arterial blood P adv , perimeter of the adventitia P bm , perimeter of the basement membrane P inep , internal perimeter of the epithelium P ism , inner perimeter of the smooth muscle layer P osm: , outer perimeter of the smooth muscle layer SaO 2 , arterial oxygen saturation IUGR, intrauterine growth restriction Low birth weight is now recognized to be a risk factor for impaired lung function during postnatal life. A growing body of epidemiologic evidence suggests that intrauterine factors that retard fetal growth and lead to low birth weight can adversely affect lung function during infancy (1-3), childhood (4 -6), and adulthood (7,8). It has been suggested that factors that restrict fetal growth, such as reduced placental delivery of nutrients and oxygen to the fetus, may alter the development of the pulmonary airways and that these changes may persist into later life (9, 10). In a study of people born during the Dutch famine of 1944 -1945, an association was show...

Effect of Nω-Nitro-l-Arginine Methyl Ester–Induced Intrauterine Growth Restriction on Postnatal Lung Growth in Rats

“…uteroplacental embolization in pregnant ewes, caused impairments in bronchial growth (27) at birth and significantly reduced functional residual capacity, total lung capacity at 30 cm H 2 O, diffusing capacity of the lung for carbon monoxide, and compliance of the respiratory system from birth to 8 wk of postnatal age in lambs (28). Moreover, gas exchange surface area, oxygen uptake, and body weight are strongly correlated in mammals (29).…”

Effects of maternal food restriction on offspring lung extracellular matrix deposition and long term pulmonary function in an experimental rat model

“…Although the molecular mechanisms underlying this respiratory compromise are not well established, general cellular and molecular effects of IUGR on the developing lung have been described. 4–15 These include an overall reduction in lung weight, DNA, and protein content, 4–6 reduced surfactant content and activity, 7–9 impaired maturation of the alveolar type II (ATII) cell, 10 decreased alveolar formation, 11–13,15 reduced alveolar surface area for gas exchange, 11,14 an immature and thicker air-blood barrier, and a thicker alveolar wall. 10,14 …”

Developmental regulation of the lung in preparation for life after birth: hormonal and nutritional manipulation of local glucocorticoid action and uncoupling protein–2

“…Interestingly, adaptations of this type in adipose tissue can affect obesity (Seckl et al 2004); in sheep, they follow the increase in fat mass with age (Bispham et al 2005). Also in sheep, maternal nutrient restriction in late gestation reduces lung growth (Harding & Johnston 1995, Symonds et al 1995 and impairs the growth of the bronchial walls, possibly affecting airway compliance in the immediate postnatal period (Wignarajah et al 2002). Increased UCP2 mRNA abundance within the lung may underlie the impairment of lung growth and function, by increased intracellular ROS production, activation of macrophages and secretion of proinflammatory cytokines, including TNF-and IL-1 (Pecqueur et al 2001, Alves-Guerra et al 2003.…”

“…Increased UCP2 mRNA abundance within the lung may underlie the impairment of lung growth and function, by increased intracellular ROS production, activation of macrophages and secretion of proinflammatory cytokines, including TNF-and IL-1 (Pecqueur et al 2001, Alves-Guerra et al 2003. Impaired pulmonary defence mechanisms may result from undernutrition (Bellanti et al 1997), possibly contributing to greater susceptibility to respiratory infections, especially since the development of mucous elements remains altered in the postnatal lung after restricted fetal growth in late gestation (Wignarajah et al 2002). The enhanced UCP2 mRNA abundance may also increase susceptibility to infection and death, as demonstrated with Toxoplasma gondii (Arsenijevic et al 2000).…”