Maternal Betamethasone and Chorioamnionitis Induce Different Collagenases during Lung Maturation in Fetal Sheep
ABSTRACT Fetal lung maturation occurs after both maternal corticosteroid administration and chorioamnionitis. The effectors of this antenatally-induced lung maturation are not understood. Matrix metalloproteinases (MMPs) 2 and 9 are type-IV collagenases that can degrade alveolar basement membranes.
We hypothesized that the structural changes of lung maturation by both antenatal corticosteroid treatment and chorioamnionitis would be associated with increases in these MMPs.
64 pregnant ewes were randomly assigned to one of four treatment groups: intra-amniotic injection of 10 mg endotoxin, maternal intramuscular injection of 0.5 mg/kg betamethasone, both treatments combined or saline-treated controls. We quantified MMP-2 which is derived from connective tissue and MMP-9 which is predominantly derived from neutrophils in fetal lung fluid of lambs after maternal corticosteroid therapy and induction of chorioamnionitis and the combination of both therapies given at 109-111 days' gestational age with delivery 1, 5 or 15 days later.
Betamethasone, endotoxin and the combined treatments increased both surfactant pool size, lung gas volume and reduced alveolar wall thickness at 15 days. MMP-2 concentration was increased after betamethasone. MMP-9 concentration increased after endotoxin-induced chorioamnionitis but decreased by the combined treatments.
Lung maturation via different pathways may use different forms of collagenases for remodelling lung structure.
- SourceAvailable from: Graeme R Polglase
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- " be a major confounder of our study . We have recently shown that the physiological transition at birth is not different between males and females ( Polglase et al . 2012a ) . Furthermore , a recent analysis of data from a series of studies in sheep ( Kramer et al . 2001 , 2005 , 2007 , 2009 ; Kallapur et al . 2007 , 2009 ; Kunzmann et al . 2007 ; Sweet et al . 2008 ; Kunzmann et al . 2010 ) showed no differences in lung structural effects or inflammatory responses between male and female fetal sheep ( Lambermont et al . 2012 ) . Alterations in pulmonary and cerebral haemodynamics observed in our study may contribute to the increased incidence of chronic lung disease and neurodevelopmental abnormal"
ABSTRACT: Background: Intrauterine inflammation impairs fetal pulmonary vascular development and increases cerebral metabolic rate in fetal sheep. We hypothesized that these structural and metabolic effects of intrauterine inflammation would be accompanied by reduced fetal pulmonary blood flow and increased cerebral perfusion. Methods: Fetal sheep were instrumented at 112 days of gestation (d: term is 147 days) for measurement of cardiopulmonary and cerebral haemodynamics. At 118 d ewes were randomly assigned to receive intra-amniotic lipopolysaccharide (LPS, 20 mg from E. coli; n=7); or saline (control; 4mL n=6. Fetal haemodynamic data were recorded continually from 0.5 hours before intra-amniotic LPS or saline, until 144 hours after. Fetal arterial blood was sampled before, and periodically after, intra-amniotic LPS or saline. Results: End-diastolic and mean pulmonary blood flows were significantly lower than control from 48 and 96 hours after LPS-exposure, respectively, until the end of the experiment. Carotid blood flow was transiently increased at 96 and 120 hours after LPS-exposure. Carotid arterial oxygen content was lower than control from 48 hours after intra-amniotic LPS. Fetal arterial lactate concentration was higher than control between 4 and 12 hours after intra-amniotic LPS. Conclusion: Experimental intrauterine inflammation reduces pulmonary blood flow in fetal sheep, over a time course consistent with impaired pulmonary vascular development. Increased carotid blood flow after LPS administration may reflect an inflammation-induced increase in cerebral metabolic demand.The Journal of Physiology 07/2013; 591(20). DOI:10.1113/jphysiol.2013.259119 · 5.04 Impact Factor
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ABSTRACT: We review information about how the preterm lung can be injured with the initiation of mechanical ventilation at birth. Although multiple variables such as pressure, tidal volume, positive end expiratory pressure, and the gas used for ventilation may contribute to the injury, the relative contribution of each is not known. Recent studies demonstrate that injury caused by initial high tidal volume is amplified by subsequent mechanical ventilation. A model for gas inflation of the fluid-filled lung may explain why even low tidal volumes may injure the preterm lung, and why the injury may initially occur to the small airways. Ventilation strategies that minimize injury need to be developed.Neonatology 02/2008; 94(3):190-6. DOI:10.1159/000143721 · 2.65 Impact Factor
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ABSTRACT: We investigated matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels in the cord blood of 29 premature infants who were <30 weeks gestation. One, 8, and 14 infants developed severe, moderate and mild bronchopulmonary dysplasia (BPD), respectively, and 6 did not. MMP-9 and TIMP-1 levels in the cord blood were determined by ELISA. MMP-9/TIMP-1 ratios in the cord blood of infants who developed severe or moderate BPD (n = 9) were significantly higher than those who developed mild BPD or did not develop BPD (n = 20; P = 0.015). Multivariate linear regressions demonstrated that MMP-9 levels and MMP-9/TIMP-1 ratios in the cord blood of the premature infants correlated with the oxygen supplementation period (r = 0.58, P = 0.003 and r = 0.41, P = 0.030, respectively). The MMP-9 levels and MMP-9/TIMP-1 ratios correlated with the severity of maternal chorioamnionitis (both trend P = 0.006). The MMP-9 levels and MMP-9/TIMP-1 ratios in the cord blood may be related to the pathogenesis and severity of BPD and maternal chorioamnionitis.Pediatric Pulmonology 03/2009; 44(3):267-72. DOI:10.1002/ppul.20993 · 2.70 Impact Factor