Antenatal Endotoxin and Glucocorticoid Effects on Lung Morphometry in Preterm Lambs

Abstract

In utero inflammation may accelerate fetal lung maturation but may also play a role in the pathogenesis of chronic lung disease. We examined the impact of endotoxin, a potent proinflammatory stimulus, on structural and functional maturation of preterm sheep lungs. Date bred ewes received 20 mg Escherichia coli endotoxin or saline by ultrasound guided intra-amniotic injection at 119 d gestation. A comparison group of animals received 0.5 mg/kg betamethasone, a known maturational agent, at 118 d gestation. Lambs were delivered by cesarean section at 125 d (term = 150 d) and ventilated for 40 min. Lung function data are reported elsewhere. Total and differential white cell counts were performed on amniotic fluid and fetal lung fluid samples. Morphometric analyses were performed on inflation fixed right upper lobes. Total cell count increased slightly but not significantly in both amniotic fluid and fetal lung fluid. Both endotoxin and betamethasone had similar effects on alveolarization: average alveolar volume increased by approximately 20% and total alveolar number decreased by almost 30%. Both treatments led to thinning of alveolar walls, although this was statistically significant in the betamethasone-treated group only. Although antenatal endotoxin leads to striking improvements in postnatal lung function, this may be at the expense of normal alveolar development.

Pulmonary and Systemic Endotoxin Tolerance in Preterm Fetal Sheep Exposed to Chorioamnionitis

“…We also reported that structural changes resembling bronchopulmonary dysplasia (fewer alveoli, vascular injury responses) occur in the preterm fetal lung after exposure to a single injection of intra-amniotic LPS (10,11). However, to our surprise, fetal lambs exposed to repeated injections of intra-amniotic LPS had lung morphology indistinguishable from gestation-matched controls when delivered close to term gestation (12).…”

Toll‐like receptor signaling inhibits structural development of the distal fetal mouse lung

“…Previous studies using animal models of bronchopulmonary dysplasia and human autopsy specimens have described alterations in lung cell matrix proteins, cellular differentiation, and alveolar structure (Bland et al, 2003;Coalson, 2003;Kaarteenaho-Wiik et al, 2004). LPS appears to also cause alveolar simplification in fetal sheep, possibly arising from decreased distal airway branching and septation (Willet et al, 2000).…”

Antenatal inflammation and lung injury: prenatal origin of neonatal disease

“…The major difference was the much larger increase in surfactant induced by endotoxin. 38,45 Maternal betamethasone caused fetal growth restriction and fetal thymic involution but intra-amniotic endotoxin did not. 64 Betamethasone suppressed lung inflammation induced by endotoxin for about 2 days.…”

“…37 By 7 days the medial thickness of arteriolar walls had increased, alveolar size had increased and alveolar number had decreased relative to controls. 38 The role of transforming growth factor-b1 (TGF-b1) was studied in the chorioamnionitis model after intra-amniotic endotoxin injection. TGF-b1 is a key regulator of lung development, lung inflammation, wound healing and remodeling, which all contribute to the development of BPD and may be involved in lung maturation after maternal steroid therapy.…”