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 ϳ147 days). From 95-133 DGA, ewes were given a 1-h daily infusion of either 0.75 g ethanol/kg (n ϭ 9) or saline (n ϭ 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 ␣1 mRNA levels (P Ͻ 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 Ͻ 0.05). The mRNA levels of the proinflammatory cytokines interleukin (IL)-1␤ and IL-8 were also lower (P Ͻ 0.05) in ethanol-exposed fetuses compared with controls. Pulmonary malondialdehyde levels tended to be increased (P ϭ 0.07) in ethanolexposed 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.

Cerebrovascular lesions, mainly germinal matrix hemorrhage and ischemic injury to the periventricular white matter, are major causes of adverse neurodevelopmental outcome in preterm infants. Cerebrovascular lesions and neuromorbidity increase with decreasing gestational age, with the white matter predominantly affected. Developmental immaturity in the cerebral circulation, including ongoing angiogenesis and vasoregulatory immaturity, plays a major role in the severity and pattern of preterm brain injury. Prevention of this injury requires insight into pathogenesis. Cerebral blood flow (CBF) is low in the preterm white matter, which also has blunted vasoreactivity compared with other brain regions. Vasoreactivity in the preterm brain to cerebral perfusion pressure, oxygen, carbon dioxide, and neuronal metabolism is also immature. This could be related to immaturity of both the vasculature and vasoactive signaling. Other pathologies arising from preterm birth and the neonatal intensive care environment itself may contribute to impaired vasoreactivity and ineffective CBF regulation, resulting in the marked variations in cerebral hemodynamics reported both within and between infants depending on their clinical condition. Many gaps exist in our understanding of how neonatal treatment procedures and medications have an impact on cerebral hemodynamics and preterm brain injury. Future research directions for neuroprotective strategies include establishing cotside, real-time clinical reference values for cerebral hemodynamics and vasoregulatory capacity and to demonstrate that these thresholds improve long-term outcomes for the preterm infant. In addition, stimulation of vascular development and repair with growth factor and cell-based therapies also hold promise.

In most species including man, cardiomyocytes cease proliferating soon after birth when they become terminally differentiated. A reduced complement of cardiomyocytes in infancy may adversely impact on the function and adaptive capabilities of the heart in later life. Low birthweight is associated with an increased risk of heart disease in adults, but little is known about its effect on the number of cardiomyocytes. Using naturally occurring differences in birthweight, our aim was to determine the effect of birthweight on cardiomyocyte number in postnatal lambs. At 9 weeks after term birth, when the final number of cardiomyocytes is considered to be established, hearts were collected at necropsy from seven singleton and seven twin lambs. Hearts were perfusion-fixed, and tissue samples were systematically taken from the left ventricle plus intraventricular septum (LV1S) and the right ventricle (RV). The number of cardiomyocyte nuclei was estimated using an unbiased optical disector-fractionator stereological technique, and the total number of cardiomyocytes was determined. Weights of the total heart, LV1S and RV were significantly related to both birthweight and necropsy weight. In the LV1S but not the RV, cardiomyocyte number was significantly and directly related to heart tissue weight, birthweight, and necropsy weight. We conclude that the final number of cardiomyocytes in the LV1S is related to prenatal and early postnatal growth, and is proportionate to the weight of heart tissue. A low cardiomyocyte number in the LV1S following restricted fetal growth may contribute to the increased incidence of heart disease in adults born with low birthweight.

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 ϭ 6) or 15 days (long-term group, 140 days GA, n ϭ 5) after MV; controls were unventilated (n ϭ 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)-1␤, IL-6, IL-8, tumor necrosis factor-␣, and transforming growth factor-␤] 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.ventilator induced lung injury; bronchopulmonary dysplasia; repair; inflammation; preterm birth VERY PRETERM INFANTS OFTEN require mechanical ventilation (MV) due to respiratory insufficiency. However, respiratory support including MV can injure the immature lung and contribute to the development of bronchopulmonary dysplasia (BPD) (10). Structural changes in the lung that are associated with MV and BPD can persist, resulting in deficits in lung function in children (17,19) and young adults (18). Consistent with this, exercise capacity is reduced in children (23, 32) and adolescents (31, 33) who were born very preterm and developed BPD. The structural changes seen in the lungs of infants with BPD include hypercellularity, fewer and larger alveoli, altered vascular growth, and disorganized elastin and collagen deposition (12). In addition, alterations to the small conducting airways have been reported in BPD-affected infants, including increases in airway smooth muscle and the number of goblet cells (47).The causes of BPD remain unclear. While MV is known to be a significant contributor to BPD, other factors are thought to be involved, including infection, use of supplemental oxygen, and impaired nutrition (27). Indeed it has been difficult to identify the role of MV alone, or any othe...

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