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Postnatal dexamethasone increases relative expression of surfactant protein messenger RNA in a preterm ventilated lamb model

Presented at the Neonatal Society 2017 Autumn Meeting.

Davis JW1, Noble PB1,2, Ahmadi-Noorbakhsh S1,2, Dah MJ3, Albertine KH3, Papagianis P2,4, Pillow JJ1,2

1 Centre for Neonatal Research and Education, University of Western Australia, Perth, WA, Australia
2 School of Human Sciences, University of Western Australia, Perth, WA, Australia
3 Dept of Pediatrics, University of Utah, Salt Lake City, UT, USA
4 The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia

Background: Postnatal dexamethasone (DEX) facilitates weaning from mechanical ventilation and the treatment of bronchopulmonary dysplasia in extremely preterm infants. DEX treatment is controversial due to neurodevelopmental concerns. The effect of low-dose DEX on lung development is unknown. We aimed to assess the effect of postnatal low-dose dexamethasone on surfactant protein (SP), inflammatory and developmental mRNA expression within the lung parenchyma of ventilated preterm lambs.

Methods: Preterm lambs exteriorised at 129d gestation after 48h exposure to maternal betamethasone were intubated and administered surfactant prior to delivery, resuscitation and volume-targeted ventilation (~6 mL/kg). Respiratory support was weaned as tolerated from invasive to non-invasive support and unassisted breathing. Postnatal lambs were assigned randomly to saline (SAL, 1 mL/kg bd; n=8) or DEX (0.15mg/kg x 3d, 0.1mg/kg x 2d, 0.05mg/kg x 2d; n=9); commencing within 2h of birth. Lambs were euthanised on d7. Naïve end-point fetal controls (n=6) were exteriorised at 136d and euthanised immediately. Surfactant protein (SP), anti-inflammatory (IL-10), proinflammatory (IL-1α, IL-1β TNF), and developmental (CTGF, EGR 1, CYR61) gene mRNA expression was measured using Fluidigm Biomark HD Taqman assay from lung tissue homogenates. mRNA expression was calculated relative to housekeeping gene (18S) in the fetal control. Ethics approval 3/100/1301.

Results: Gestation, birth weight, and sex ratio did not differ between study groups. Relative to fetal controls, postnatal lambs had increased mRNA expression for SP-A (p=0.001), SP-B (p=0.003), SP-C (p=0.01), IL-10 (p<0.001), IL- 1α (p=0.001), IL-1β (p=0.001), TNF (p<0.001), CTGF (p=0.002), EGR1 (p=0.001) and CYR61 (p=0.024). Compared to saline, DEX increased relative mRNA expression of SP-A (median, inter quartile range (IQR) 27.3 (14.7 – 45.5) vs 164 (71.8 – 526), p<0.001) and SP-C (7.7 (5.2 – 9.4) vs 13.1 (7.8 – 34.9), p=0.030). There was a similar trend for DEX to increase SP-B mRNA expression (20.0 (11.6 – 42.1) in saline controls vs 33.5 (19.4 – 22.9) with DEX, p=0.09). mRNA expression did not differ between SAL and DEX postnatal lamb groups for IL-10 (p=0.34), IL-1α (p=0.96), IL-1β (p=0.23), TNF (p=0.57), CTGF (p=0.13), EGR1 (p=0.96) or CRY61 (p=0.67).

Conclusion: Ventilated preterm lambs receiving a 7 day course of low-dose dexamethasone commencing within 2 hours of birth upregulate mRNA expression of surfactant protein A and C compared to saline placebo and fetal controls. mRNA expression of inflammatory proteins and growth factors increase after birth but are not affected by lowdose dexamethasone exposure.

Corresponding author: jonathan.davis@uwa.edu.au

Acknowledgement
This study was funded through the National Health Research Council (Australia) (GRT1057759, GRT1077691, and GRT1057514).

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