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PPARγ activation in late gestation does not promote surfactant maturation in the fetal sheep lung

Published online by Cambridge University Press:  07 January 2021

Jiaqi Ren
Affiliation:
Department of Physiology, University of Toronto, Toronto, ON, Canada Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia Hospital for Sick Children, Toronto, ON, Canada
Mitchell C. Lock
Affiliation:
Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
Jack R. T. Darby
Affiliation:
Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
Sandra Orgeig
Affiliation:
Cancer Research Institute, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
Stacey L. Holman
Affiliation:
Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
Megan Quinn
Affiliation:
Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
Mike Seed
Affiliation:
Department of Physiology, University of Toronto, Toronto, ON, Canada Hospital for Sick Children, Toronto, ON, Canada
Beverly S. Muhlhausler
Affiliation:
CSIRO, University of Adelaide, Adelaide, SA, Australia
I. Caroline McMillen
Affiliation:
Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
Janna L. Morrison*
Affiliation:
Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
*
Address for correspondence: Janna L. Morrison, Australian Research Council Future Fellow, Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, GPO Box 2471, Adelaide, SA, Australia5001. Email: Janna.Morrison@unisa.edu.au

Abstract

Respiratory distress syndrome results from inadequate functional pulmonary surfactant and is a significant cause of mortality in preterm infants. Surfactant is essential for regulating alveolar interfacial surface tension, and its synthesis by Type II alveolar epithelial cells is stimulated by leptin produced by pulmonary lipofibroblasts upon activation by peroxisome proliferator-activated receptor γ (PPARγ). As it is unknown whether PPARγ stimulation or direct leptin administration can stimulate surfactant synthesis before birth, we examined the effect of continuous fetal administration of either the PPARγ agonist, rosiglitazone (RGZ; Study 1) or leptin (Study 2) on surfactant protein maturation in the late gestation fetal sheep lung. We measured mRNA expression of genes involved in surfactant maturation and showed that RGZ treatment reduced mRNA expression of LPCAT1 (surfactant phospholipid synthesis) and LAMP3 (marker for lamellar bodies), but did not alter mRNA expression of PPARγ, surfactant proteins (SFTP-A, -B, -C, and -D), PCYT1A (surfactant phospholipid synthesis), ABCA3 (phospholipid transportation), or the PPARγ target genes SPHK-1 and PAI-1. Leptin infusion significantly increased the expression of PPARγ and IGF2 and decreased the expression of SFTP-B. However, mRNA expression of the majority of genes involved in surfactant synthesis was not affected. These results suggest a potential decreased capacity for surfactant phospholipid and protein production in the fetal lung after RGZ and leptin administration, respectively. Therefore, targeting PPARγ may not be a feasible mechanistic approach to promote lung maturation.

Type
Original Article
Copyright
© The Author(s), 2021. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

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PPARγ activation in late gestation does not promote surfactant maturation in the fetal sheep lung
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