Abstract
BackgroundPrenatal glucocorticoid treatment decreases alveolar tissue volumes and facilitates fetal lung maturation, however the mechanisms responsible are largely unknown. This study examines whether changes in versican levels or sulphation patterns of chondroitin sulphate (CS) side chains, are associated with glucocorticoid-induced reductions in peri-alveolar tissue volumes.MethodsLung tissue was collected from 1) fetal sheep at 131 ± 0.1 days gestational age (GA) infused with cortisol (122-131d GA) to prematurely induce a pre-parturient-like rise in circulating cortisol, 2) fetal sheep at 143d GA bilaterally adrenalectomised (ADX) at 112d GA to remove endogenous cortisol and 3) fetal sheep at 124d GA in which bolus doses (2 × 11.4 mg) of betamethasone were administered to the pregnant ewe. The level and distribution of versican and CS glycosaminoglycans (GAG) were determined using immunohistochemistry (IHC). Fluorophore assisted carbohydrate electrophoresis (FACE) was used to determine changes in CS sulphation patterns.ResultsCortisol infusion significantly decreased chondrotin-6-sulphate levels (C-6-S) to 16.4 ± 0.7 AU, compared with saline-infused fetuses (18.9 ± 0.7 AU: p = 0.04) but did not significantly alter the level of versican or chondroitin-4-sulphate (C-4-S). ADX significantly increased the level of C-4-S (28.2 ± 2.2 AU), compared with sham-operated fetuses (17.8 ± 2.0 AU; p = 0.006) without altering versican or C-6-S levels. Betamethasone significantly decreased versican, C-4-S and C-6-S in the fetal sheep lung (19.2 ± 0.9 AU, 24.9 ± 1.4 AU and 23.2 ± 1.0 AU, respectively), compared with saline-exposed fetuses (24.3 ± 0.4 AU, p = 0.0004; 33.3±0.6 AU, p = 0.0003; 29.8±1.3 AU, 0.03, respectively).ConclusionsThese results indicate that glucocorticoids alter versican levels and CS side chain microstructure in alveolar lung tissue. Betamethasone appears to have a greater impact on versican and CS side chains than cortisol.
Highlights
Prenatal glucocorticoid treatment decreases alveolar tissue volumes and facilitates fetal lung maturation, the mechanisms responsible are largely unknown
In addition to showing that versican levels are closely associated with changes in lung tissue volumes during development, we have shown marked changes in the microstructure of chondroitin sulphate (CS) side chains in lung tissue during development [10]
The mechanisms responsible for these changes in versican levels are unknown, it is possible that endogenous cortisol, which is known to mature the fetal lung in late gestation, may be involved [11]
Summary
Prenatal glucocorticoid treatment decreases alveolar tissue volumes and facilitates fetal lung maturation, the mechanisms responsible are largely unknown. The mechanisms and specific ECM components involved remain largely unknown we have recently shown that versican is a target of glucocorticoid signalling in the developing lung [11]. Variations in the position and degree of sulphation within GAGs create substantial structural and functional diversity for CS proteoglycans. Alterations in the structural properties of versican, leading to changes in its anionic charge density, may regulate tissue volumes and viscoelastic properties of the distal airways in the developing lung. The mechanisms responsible for these changes in versican levels are unknown, it is possible that endogenous cortisol, which is known to mature the fetal lung in late gestation, may be involved [11]
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