R Harding

Monash University (Australia), Melbourne, Victoria, Australia

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Publications (246)585.43 Total impact

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    ABSTRACT: Preterm infants who receive supplemental oxygen for prolonged periods are at increased risk of impaired lung function later in life. This suggests that neonatal hyperoxia induces persistent changes in small conducting airways (bronchioles). Although the effects of neonatal hyperoxia on alveolarization are well documented, little is known about its effects on developing bronchioles. We hypothesized that neonatal hyperoxia would remodel the bronchiolar walls, contributing to altered lung function in adulthood. We studied three groups of mice (C57BL/6J) to postnatal day 56 (P56; adulthood) when they either underwent lung function testing or necropsy for histological analysis of the bronchiolar wall. One group inhaled 65% O2 from birth until P7, after which they breathed room air; this group experienced growth restriction (HE+GR group). We also used a group in which hyperoxia-induced GR was prevented by dam rotation (HE group). A control group inhaled room air from birth. At P56, the bronchiolar epithelium of HE mice contained fewer Clara cells and more ciliated cells, and the bronchiolar wall contained ∼25% less collagen than controls; in HE+GR mice the bronchiolar walls had ∼13% more collagen than controls. Male HE and HE+GR mice had significantly thicker bronchiolar epithelium than control males and altered lung function (HE males: greater dynamic compliance; HE+GR males: lower dynamic compliance). We conclude that neonatal hyperoxia remodels the bronchiolar wall and, in adult males, affects lung function, but effects are altered by concomitant growth restriction. Our findings may partly explain the reports of poor lung function in ex-preterm children and adults. Anat Rec, 2014. © 2014 Wiley Periodicals, Inc.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 01/2014; · 1.34 Impact Factor
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    ABSTRACT: ABSTRACT Preterm male infants have a higher incidence of morbidity and mortality due to respiratory insufficiency than females of the same gestational age. This male disadvantage could be due to differences in lung architecture; however, few studies have compared lung architecture in male and female fetuses during late gestation. Our principal objectives were to compare the morphology of the fetal lung and the maturity of the surfactant system in preterm male and female fetuses. Lungs from male (n = 9) and female (n = 11) fetal sheep were collected at 0.9 of term (131 days of the 145-day gestation) for morphological and molecular analyses. In separate groups, tracheal liquid was obtained from male (n = 9) and female (n = 9) fetuses at 0.9 of term for determination of surfactant phospholipid composition. We found no sex-related differences in body weight, lung weight, right lung volume, lung tissue and airspace fractions, mean linear intercept, septal crest density, septal thickness, the proportion of proliferating and apoptotic cells, and the percentages of collagen or elastin. The gene expression of surfactant protein -A, -B, -C, and -D and tropoelastin was similar between sexes. There were no differences in the proportion of the major phospholipid classes in the tracheal liquid between sexes; however there was a significantly higher percentage of the phospholipid species phosphatidylinositol 38:5 in males. The greater morbidity and mortality in preterm male lambs do not appear to be related to differences in lung structure or surfactant phospholipid synthesis before birth, but may relate to physiological adaptation to air-breathing at birth.
    Experimental Lung Research 12/2013; · 1.47 Impact Factor
  • Megan O'Reilly, Richard Harding, Foula Sozo
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    ABSTRACT: Background: Supplemental oxygen is necessary in the respiratory support of very preterm infants, but it may contribute to bronchopulmonary dysplasia and an increased risk of poor lung function in later life. It is well established that hyperoxia can inhibit alveolarization, but effects on the developing conducting airways, which are important determinants of lung function, are poorly understood. It is possible that prolonged exposure of the immature lung to hyperoxic gas alters the development of small conducting airways (bronchioles), and that these effects may persist throughout life. Objectives: To examine the effects of neonatal inhalation of hyperoxic gas on the bronchiolar walls in adulthood. Methods: Neonatal mice (C57BL/6J) born at term inhaled 65% O2 from birth until postnatal day 7; thereafter, they were raised in room air until 10 months postnatal age (P10mo), which is advanced adulthood. Age-matched controls inhaled room air from birth. We investigated small conducting airways with a diameter between 105-310 µm. Results: At P10mo, bronchiolar walls of hyperoxia-exposed mice contained ∼18% more smooth muscle than controls (p < 0.05), although there was no effect on bronchiolar epithelium or collagen. Neonatal hyperoxia resulted in significantly fewer bronchiolar-alveolar attachments at P10mo (p < 0.05); this was accompanied by persistent simplification of the lung parenchyma, as indicated by greater mean linear intercept and less parenchymal tissue (p < 0.05). Conclusions: Neonatal exposure to hyperoxia induces remodeling of the bronchiolar walls and loss of bronchiolar-alveolar attachments in adulthood, both of which could contribute to impaired lung function and airway hyper-reactivity. © 2013 S. Karger AG, Basel.
    Neonatology 11/2013; 105(1):39-45. · 2.57 Impact Factor
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    Fetal Alcohol Canadian Expertise (FACE) Research Association, St. John's Newfoundland; 09/2013
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    ABSTRACT: High levels of alcohol (ethanol) exposure during fetal life can affect liver development and can increase susceptibility to infection after birth. Our aim was to determine the effects of a moderate level of ethanol exposure in late gestation on the morphology, iron status and inflammatory status of the ovine fetal liver. Pregnant ewes were chronically catheterized at 91 days of gestation (DG; term ~145DG) for daily I.V. infusion of ethanol (0.75g/kg maternal body weight, n=8) or saline (n=7) over 1h from 95-133DG. At necropsy (134DG), fetal livers were collected for analysis. Liver weight, general liver morphology, hepatic cell proliferation and apoptosis, perivascular collagen deposition, and interleukin (IL)-1β, IL-6 or IL-8 mRNA levels were not different between groups. However, ethanol exposure led to significant decreases in hepatic content of ferric iron and gene expression of the iron-regulating hormone hepcidin and tumor necrosis factor (TNF)-α (all P<0.05). In the placenta, there was no difference in transferrin receptor, divalent metal transporter 1 and ferritin mRNA levels; however, ferroportin mRNA levels were increased in ethanol-exposed animals (P<0.05) and ferroportin protein tended to be increased (P=0.054). Plasma iron concentration was not different between control and ethanol-exposed groups; control fetuses had significantly higher iron concentrations than their mothers, whereas maternal and fetal iron concentrations were similar in ethanol-exposed animals. We conclude that daily ethanol exposure during the third-trimester-equivalent in sheep does not alter fetal liver morphology; however, decreased fetal liver ferric iron content and altered hepcidin and ferroportin gene expression indicate that iron homeostasis is altered.
    AJP Regulatory Integrative and Comparative Physiology 04/2013; · 3.28 Impact Factor
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    ABSTRACT: A reduced nephron endowment early in life adversely impacts on long-term functional reserve in the kidney. A recent study has shown that acute exposure to chorioamnionitis during late gestation can adversely impact on nephrogenesis. The present study aimed to examine the effects of chronic, low-dose endotoxin exposure in utero, during the period of nephrogenesis, on nephron number and glomerular size in preterm lambs. Ewes were administered either: endotoxin (lipopolysaccharide, LPS; 1mg/day) or saline at 110 to 133 days of gestation (term ~147 days) via surgically implanted osmotic mini-pumps within the amniotic cavity. The ewes were induced to deliver preterm at 133 days gestation and the kidneys of the lambs were analysed at 8 weeks post term-equivalent age. Nephron number per kidney was determined using an unbiased optical disector/fractionator stereological approach; renal corpuscle size was also stereologically measured. At 8 weeks after term-equivalent age there was no significant effect of in utero exposure of endotoxin on body weight or kidney weight and there were no significant differences in nephron number, nephron density, or renal corpuscle volume between groups. We conclude that chronic intrauterine inflammation during the period of nephrogenesis may not adversely impact on the number of nephrons formed within the kidney or on the volume of the renal corpuscle. This article is protected by copyright. All rights reserved.
    Clinical and Experimental Pharmacology and Physiology 04/2013; · 2.16 Impact Factor
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    ABSTRACT: Preterm neonates are born while nephrogenesis is ongoing and are commonly exposed to factors in the extrauterine environment that may impair renal development. Supplemental oxygen therapy exposes the preterm infant to a hyperoxic environment which may induce oxidative stress. Our aim was to determine the immediate and long-term effects of exposure to hyperoxia, during the period of postnatal nephrogenesis, on renal development. Newborn mice (C57BL/6J) were kept in a normoxic (room air, 21% oxygen) or a controlled hyperoxic (65% oxygen) environment from birth to postnatal day 7 (P7d). From P7d, animals were maintained in room air until early adulthood at postnatal day 56 (P56d) or middle age (10 months; P10mo). Pups were assessed for glomerular maturity and renal corpuscle cross-sectional area at P7d (control n=14; hyperoxic n=14). Nephron number and renal corpuscle size were determined stereologically at P56d (control n=14; hyperoxic n=14) and P10mo (control n=10; hyperoxic n=10). At P7d, there was no effect of hyperoxia on glomerular size or maturity. In early adulthood (P56d) body weights, relative kidney weights and volumes, and nephron number were not different between groups, but the renal corpuscles were significantly enlarged. This was no longer evident at P10mo, with relative kidney weights and volumes, nephron number and renal corpuscle size not different between groups. Furthermore, hyperoxia-exposure did not significantly accelerate glomerulosclerosis in middle age. Hence, our findings show no overt long-term deleterious effects of early life hyperoxia on glomerular structure.
    AJP Renal Physiology 02/2013; · 4.42 Impact Factor
  • Megan O'Reilly, Foula Sozo, Richard Harding
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    ABSTRACT: Preterm birth affects 8-10% of human pregnancies and is a major cause of long-term disability. Individuals who are born very preterm, especially if they develop bronchopulmonary dysplasia (BPD), have an increased risk of impaired lung function in infancy, childhood and adulthood, and an increased risk of respiratory illness. Our aim is to briefly review current understanding of the basis for long-term impairments in lung function and respiratory health following preterm birth and BPD. Histopathology of the lungs of infants and children following preterm birth and BPD show altered development of the lung parenchyma, conducting airways and pulmonary vasculature. Owing to improvements in the care of preterm infants, especially the use of exogenous surfactant and lower concentrations of administered oxygen, lung pathology following preterm birth and BPD is less severe than in the past. Recent studies indicate that very preterm birth and BPD can lead to hyperplasia of airway smooth muscle, impaired alveolarization, pulmonary inflammation and an increase in pulmonary artery muscularization. Imaging of adult lungs suggests that the deficit in alveoli can persist into later life. Long-term lung injury apparently relates to the use of mechanical ventilation and the use of supplemental oxygen in infancy. Impaired lung function in later life is due to airway hyper-reactivity and fewer alveoli, resulting in reductions in the surface area for gas exchange and physical support for bronchioles. As the incidence of preterm birth is not declining it will continue to be a major cause of respiratory ill-health in adults. © 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.
    Clinical and Experimental Pharmacology and Physiology 02/2013; · 2.16 Impact Factor
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    ABSTRACT: Extremely preterm infants often receive mechanical ventilation (MV), which can contribute to bronchopulmonary dysplasia (BPD). However, the effects of MV alone on the extremely preterm lung and the lung's capacity for repair are poorly understood. To characterise lung injury induced by MV alone, and mechanisms of injury and repair, in extremely preterm lungs and to compare them with very preterm lungs. Extremely preterm lambs (0.75 of term) were transiently exposed by hysterotomy and underwent 2 h of injurious MV. Lungs were collected 24 h and at 15 d after MV. Immunohistochemistry and morphometry were used to characterise injury and repair processes. qRT-PCR was performed on extremely and very preterm (0.85 of term) lungs 24 h after MV to assess molecular injury and repair responses. 24 h after MV at 0.75 of term, lung parenchyma and bronchioles were severely injured; tissue space and myofibroblast density were increased, collagen and elastin fibres were deformed and secondary crest density was reduced. Bronchioles contained debris and their epithelium was injured and thickened. 24 h after MV at 0.75 and 0.85 of term, mRNA expression of potential mediators of lung repair were significantly increased. By 15 days after MV, most lung injury had resolved without treatment. Extremely immature lungs, particularly bronchioles, are severely injured by 2 h of MV. In the absence of continued ventilation these injured lungs are capable of repair. At 24 h after MV, genes associated with injurious MV are unaltered, while potential repair genes are activated in both extremely and very preterm lungs.
    PLoS ONE 01/2013; 8(5):e63905. · 3.73 Impact Factor
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    ABSTRACT: Meconium fatty acid ethyl esters (FAEE) constitute a biomarker of heavy fetal ethanol exposure. Our objective was to measure meconium FAEE in fetal sheep following daily, relatively moderate-dose ethanol exposure in late gestation, and to evaluate their utility in identifying fetal organ-system injury. Pregnant ewes received ethanol (0.75 g/kg; n = 14) or saline (n = 8) via 1-h IV infusion daily during the third trimester equivalent, while additional pregnant sheep served as untreated controls (n = 6). The daily ethanol regimen produced similar maximal maternal and fetal plasma ethanol concentrations of 0.11-0.12 g/dL. Ewes and fetuses were euthanized shortly before term, and meconium was collected and analyzed for FAEE (ethyl palmitate, stearate, linoleate, and oleate). Meconium total FAEE concentration was significantly higher in ethanol-exposed fetuses compared with controls, and a positive cut-off of 0.0285 nmol total FAEE/g meconium had 93.3% sensitivity and specificity for detecting fetal ethanol exposure. When the studied animals (ethanol-exposed and controls) were classified according to meconium FAEE concentration, FAEE-positive and FAEE-negative groups frequently differed with respect to previously examined pathological endpoints, including nephron endowment, lung collagen deposition, cardiomyocyte maturation, and tropoelastin gene expression in cerebral vessels. Furthermore, in all studied animals as a group (ethanol-exposed and controls combined), meconium FAEE concentration was correlated with many of these pathological endpoints in fetal organs. We conclude that, in fetal sheep, meconium FAEE could serve as a biomarker of daily ethanol exposure in late gestation and could identify fetuses with subtle ethanol-induced toxic effects in various organs. This study illustrates the potential for using meconium FAEE to identify neonates at risk for dysfunction of major organs following in-utero ethanol exposure that does not result in overt physical signs of ethanol teratogenicity.
    PLoS ONE 01/2013; 8(3):e59168. · 3.73 Impact Factor
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    ABSTRACT: Male preterm infants are at greater risk of respiratory morbidity and mortality than females but mechanisms are poorly understood. Our objective was to identify the basis for the "male disadvantage" following preterm birth using an ovine model of preterm birth in which survival of females is greater than males. At 0.85 of term, fetal sheep underwent surgery (11 female, 10 male) for the implantation of vascular catheters to monitor blood gases and arterial pressure. After cesarean delivery at 0.90 of term, lambs were monitored for 4 h while spontaneously breathing; lambs were then euthanized and static lung compliance measured. We analyzed surfactant phospholipid composition in amniotic fluid and in bronchoalveolar lavage fluid (BALF) taken at necropsy; we also analyzed surfactant protein (SP) expression in lung tissue. Before delivery male fetuses tended to have lower pH (P = 0.052) compared with females. One hour after delivery, males had significantly lower pH and higher arterial partial pressure of CO(2) (Pa(CO(2))), lactate, glucose, and mean arterial pressure than females. Two males died 1 h after birth. Static lung compliance was 37% lower in males than females (P < 0.05). In BALF, males had significantly more protein, a lower percentage of the phosphatidylcholine (PC) 32:0 (dipalmitoylphosphatidylcholine) and higher percentages of PC34:2 and PC36:2. There were no sex-related differences in lung architecture or expression of SP-A, -B, -C, and -D. The lower lung compliance in male preterm lambs compared with females may be due to altered surfactant phospholipid composition and function. These changes may compromise gas exchange and impair respiratory adaptation after male preterm birth.
    AJP Regulatory Integrative and Comparative Physiology 08/2012; 303(7):R778-89. · 3.28 Impact Factor
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    ABSTRACT: Our aim was to determine whether fetal exposure to intraamniotic lipopolysaccharide (LPS) persistently alters the lungs following moderate preterm birth. Fetal sheep were exposed to LPS (1 mg/d) or saline from 0.75 to preterm birth at 0.90 of gestation. Eleven weeks after preterm birth, lung structure was unaltered. Interleukin (IL)-1β messenger RNA (mRNA) levels were elevated in lungs of LPS-exposed lambs (P < .05) but IL-1β protein levels were unaltered. Lung mRNA levels of IL-6, IL-8 and tumor necrosis factor α, and percentage of inflammatory cells were not different between groups. Surfactant protein (SP)-A and SP-C mRNA levels and SP-B tissue protein expression were higher in LPS-exposed lambs than controls (all P < .05); however, expression of SP-A and SP-C proteins was reduced. Prenatal LPS exposure causes a persistent increase in gene expression of proinflammatory mediators and surfactant proteins and a decrease in lung tissue SP-A and -C protein expression after preterm birth, which may affect lung immunity.
    Reproductive sciences (Thousand Oaks, Calif.) 08/2012; · 2.31 Impact Factor
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    ABSTRACT: Alcohol consumption during pregnancy remains common in many countries. Exposure to even low amounts of alcohol (i.e. ethanol) in pregnancy can lead to the heterogeneous fetal alcohol spectrum disorders (FASD), while heavy alcohol consumption can result in the fetal alcohol syndrome (FAS). FAS is characterized by cerebral dysfunction, growth restriction and craniofacial malformations. However, the effects of lower doses of alcohol during pregnancy, such as those that lead to FASD, are less well understood. In this article, we discuss the findings of recent studies performed in our laboratories on the effects of fetal alcohol exposure using sheep, in which we investigated the effects of late gestational alcohol exposure on the developing brain, arteries, kidneys, heart and lungs. Our studies indicate that alcohol exposure in late gestation can (1) affect cerebral white matter development and increase the risk of hemorrhage in the fetal brain, (2) cause left ventricular hypertrophy with evidence of altered cardiomyocyte maturation, (3) lead to a decrease in nephron number in the kidney, (4) cause altered arterial wall stiffness and endothelial and smooth muscle function and (5) result in altered surfactant protein mRNA expression, surfactant phospholipid composition and pro-inflammatory cytokine mRNA expression in the lung. These findings suggest that fetal alcohol exposure in late gestation can affect multiple organs, potentially increasing the risk of disease and organ dysfunction in later life.
    Journal of Developmental Origins of Health and Disease. 08/2012; 3(04).
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    ABSTRACT: Introduction:Caffeine administration is associated with a reduction in bronchopulmonary dysplasia, assisted ventilation, patent ductus arteriosus (DA) and cerebral palsy in preterm infants, but the mechanisms are unknown. Our aim was to determine the effects of acute caffeine administration on renal and pulmonary function in preterm lambs.Methods:Lambs were delivered by caesarean section at ~126 days of gestation and ventilated with a tidal volume of 5 ml/kg, 60 breaths/min and 5 cmH(2)O positive end-expiratory pressure. After 30 minutes, lambs received 40 mg/kg caffeine i.v (n=7) or saline (controls; n=6) over 30 minutes and were ventilated for 2 hours.Results:Arterial caffeine concentrations reached 35.9 ± 7.8 mg/l. Urine output was significantly higher after caffeine treatment than in controls (5.86 ± 1.95 vs 0.76 ± 0.94 ml/kg, area under curve p=0.041). Mean heart rate was significantly higher after caffeine treatment than in controls (211 ± 8 vs 169 ± 15 beats per minute, p<0.05) and remained higher for the experimental period.Discussion:Caffeine did not affect pulmonary artery or DA blood flows or other renal, respiratory or cardiovascular parameters examined. Neonatal caffeine administration increased heart rate and urine output but had little effect on pulmonary function in ventilated preterm lambs.
    Pediatric Research 04/2012; · 2.67 Impact Factor
  • Richard Harding, Gert Maritz
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    ABSTRACT: 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.
    Seminars in Fetal and Neonatal Medicine 04/2012; 17(2):67-72. · 3.51 Impact Factor
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    ABSTRACT: Males born preterm are at greater risk of illness and death than females, principally due to respiratory disease. Much of the excess morbidity occurs within the first few hours of life. Therefore, the aim of the present study was to investigate whether or not differences in the cardiopulmonary transition soon after birth underlie the increased morbidity in males after preterm birth. Nine female and thirteen male lambs (128±2 days gestation) underwent surgery immediately before delivery for implantation of a pulmonary arterial flow-probe and catheters into the main pulmonary artery and a carotid artery. After birth lambs were ventilated for 30 min (tidal volume 7 mL kg(-1)) while anaesthetised. Arterial pressures and flows were recorded in real time and left-ventricular output measured using Doppler echocardiography. Before birth, fetal cardiopulmonary haemodynamics, arterial blood gases, pH, glucose and lactate did not differ between sexes. Similarly, in the neonatal period there were no significant differences in arterial blood gas status, ventilation parameters, respiratory indices or cardiopulmonary haemodynamics between the sexes. Our data show that the cardiopulmonary transition at birth in ventilated, anaesthetised preterm lambs is not influenced by sex. Thus, the neonatal 'male disadvantage' is not explained by an impaired cardiovascular transition at birth.
    Reproduction Fertility and Development 03/2012; 24(3):510-6. · 2.58 Impact Factor
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    ABSTRACT: Preterm birth affects 8-12% of live births and is associated with the development of elevated arterial blood pressure and aortic narrowing in later life; this suggests that preterm birth may alter the development of arteries. Our objective was to determine the effects of preterm birth, accompanied by antenatal corticosteroid administration, on the structure of the aorta and pulmonary artery, which experience different alterations in pressure flow at birth. At 11 wk, preterm lambs had significantly thicker aortic walls and a smaller lumen, whereas the morphometry of the pulmonary artery was unaffected. Elastin deposition was markedly increased in the aorta and pulmonary artery and smooth muscle content was reduced in the aorta only. In preterm lambs we found injury in the aorta only; controls were unaffected. We conclude that moderate preterm birth after antenatal betamethasone can cause injury and persistent alterations in the structure and composition of the aorta, with lesser effects in the pulmonary artery. Our findings suggest that preterm birth may increase the risk of atherosclerosis and aortic aneurysms in later life. Using an established ovine model of preterm birth, lambs were born at 0.9 of gestation and underwent necropsy at 11 wk after birth; controls were born at term.
    Pediatric Research 02/2012; 71(2):150-5. · 2.67 Impact Factor
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    ABSTRACT: Mechanical ventilation (MV) of very premature infants contributes to lung injury and bronchopulmonary dysplasia (BPD), the effects of which can be long-lasting. Little is currently known about the ability of the very immature lung to recover from ventilator-induced lung injury. Our objective was to determine the ability of the injured very immature lung to repair in the absence of continued ventilation and to identify potential mechanisms. At 125 days gestational age (days GA, 0.85 of term), fetal sheep were partially exposed by hysterotomy under anesthesia and aseptic conditions; they were intubated and ventilated for 2 h with an injurious MV protocol and then returned to the uterus to continue development. Necropsy was performed at either 1 day (short-term group, 126 days GA, n = 6) or 15 days (long-term group, 140 days GA, n = 5) after MV; controls were unventilated (n = 7-8). At 1 day after MV, lungs displayed signs of injury, including hemorrhage, disorganized elastin and collagen deposition in the distal airspaces, altered morphology, significantly reduced secondary septal crest density, and decreased airspace. Bronchioles had thickened epithelium with evidence of injury and sloughing. Relative mRNA levels of early response genes (connective tissue growth factor, cysteine-rich 61, and early growth response-1) and proinflammatory cytokines [interleukins (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and transforming growth factor-β] were not different between groups 1 day after MV. At 15 days after MV, lung structure was normal with no evidence of injury. We conclude that 2 h of MV induces severe injury in the very immature lung and that these lungs have the capacity to repair spontaneously in the absence of further ventilation.
    AJP Lung Cellular and Molecular Physiology 09/2011; 301(6):L917-26. · 3.52 Impact Factor
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    ABSTRACT: High levels of ethanol (EtOH) consumption during pregnancy adversely affect fetal development; however, the effects of lower levels of exposure are less clear. Our objectives were to assess the effects of daily EtOH exposure (3.8 USA standard drinks) on fetal-maternal physiological variables and the fetal brain, particularly white matter. Pregnant ewes received daily intravenous infusions of EtOH (0.75 g/kg maternal body wt over 1 h, 8 fetuses) or saline (8 fetuses) from 95 to 133 days of gestational age (DGA; term ∼145 DGA). Maternal and fetal arterial blood was sampled at 131-133 DGA. At necropsy (134 DGA) fetal brains were collected for analysis. Maternal and fetal plasma EtOH concentrations reached similar maximal concentration (∼0.11 g/dl) and declined at the same rate. EtOH infusions produced mild reductions in fetal arterial oxygenation but there were no changes in maternal oxygenation, maternal and fetal Pa(CO(2)), or in fetal mean arterial pressure or heart rate. Following EtOH infusions, plasma lactate levels were elevated in ewes and fetuses, but arterial pH fell only in ewes. Fetal body and brain weights were similar between groups. In three of eight EtOH-exposed fetuses there were small subarachnoid hemorrhages in the cerebrum and cerebellum associated with focal cortical neuronal death and gliosis. Overall, there was no evidence of cystic lesions, inflammation, increased apoptosis, or white matter injury. We conclude that daily EtOH exposure during the third trimester-equivalent of ovine pregnancy has modest physiological effects on the fetus and no gross effects on fetal white matter development.
    AJP Regulatory Integrative and Comparative Physiology 06/2011; 301(4):R926-36. · 3.28 Impact Factor
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    Sandra Rees, Richard Harding, David Walker
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    ABSTRACT: A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fetal brain injury, abnormal brain development and in cases of chronic compromise, intrauterine growth restriction. Preterm birth can also be associated with injury to the developing brain and affect the normal trajectory of brain growth. This review will focus on the effects that episodes of perinatal hypoxia (acute, chronic, associated with inflammation or as an antecedent of preterm birth) can have on the developing brain. In animal models of these conditions we have found that relatively brief (acute) periods of fetal hypoxemia can have significant effects on the fetal brain, for example death of susceptible neuronal populations (cerebellum, hippocampus, cortex) and cerebral white matter damage. Chronic placental insufficiency which includes fetal hypoxemia, nutrient restriction and altered endocrine status can result in fetal growth restriction and long-term deficits in neural connectivity in addition to altered postnatal function, for example in the auditory and visual systems. Maternal/fetal inflammation can result in fetal brain damage, particularly but not exclusively in the white matter; injury is more pronounced when associated with fetal hypoxemia. In the baboon, in which the normal trajectory of growth is affected by preterm birth, there is a direct correlation between a higher flux in oxygen saturation and a greater extent of neuropathological damage. Currently, the only established therapy for neonatal encephalopathy in full term neonates is moderate hypothermia although this only offers some protection to moderately but not severely affected brains. There is no accepted therapy for injured preterm brains. Consequently the search for more efficacious treatments continues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of efficacious strategies for neuroprotection.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 04/2011; 29(6):551-63. · 2.03 Impact Factor

Publication Stats

3k Citations
585.43 Total Impact Points

Institutions

  • 1984–2014
    • Monash University (Australia)
      • • Department of Anatomy and Developmental Biology
      • • Ritchie Centre for Baby Health Research
      • • School of Biomedical Sciences
      • • Department of Physiology
      Melbourne, Victoria, Australia
  • 2001–2011
    • University of the Western Cape
      • • Department of Medical Biosciences
      • • Department of Physiological Sciences
      Cape Town, Province of the Western Cape, South Africa
  • 1989–2011
    • University of Melbourne
      • • Veterinary Science Library
      • • Animal Biotechnology
      Melbourne, Victoria, Australia
  • 1997–2010
    • Victoria University Melbourne
      Melbourne, Victoria, Australia
  • 2002–2006
    • University of Western Australia
      • School of Women's and Infants' Health
      Perth, Western Australia, Australia
  • 2004
    • Spokane VA Medical Center
      Spokane, Washington, United States
    • Royal Hospital for Women
      Sydney, New South Wales, Australia
  • 1994
    • Alfred Hospital
      Melbourne, Victoria, Australia
  • 1991
    • University of Cambridge
      Cambridge, England, United Kingdom