Date of Award
MSc by research (Master of Science by research)
Professor Prem Puri
Professor Carlos Blanco
Financial support from the National Children's research Centre and the Children's Medical Research Foundation.
Congenital diaphragmatic hernia (CDH) is a prenatal defect in the integrity of the developing diaphragm, which results in severe pulmonary hypoplasia (PH) with alveolar immaturity. Peroxisome proliferator-activated receptor y (PPARy) plays a key role in foetal alveolarization by coordinating alveolar cell proliferation and differentiation, which results in enhanced expression of alveolar lipid-containing interstitial fibroblasts (LIFs). Furthermore, PPARy increases the lipid content of alveolar LIFs by upregulation of adipocyte differentiation-related protein (ADRP), a lipogenic marker for alveolar mesenchymal differentiation and physiological determinant for the synthesis of surfactant phospholipids. Since PPARy transcripts and alveolar LIFs are significantly decreased in hypoplastic rat lungs, the overall aim of this work was to investigate the hypothesis that the synthetic PPARy agonist rosiglitazone (RGZ) has the potential to improve foetal alveolar development in the nitrofen rat model of CDH-associated PH.
The first objective of this work was to examine the in vitro effects of RGZ treatment in an explant culture of foetal rat lungs. Morphometric analysis revealed that daily administration of RGZ enhances alveolarization in nitrofen-exposed hypoplastic lungs compared to Placebo-treated lung explants, which was further supported by a significantly increased radial alveolar count and decreased mean linear intercept.
The second objective was to evaluate the in vivo effects of prenatally administered RGZ on alveolar development and maturation in foetal rats with CDH. lmmunohistochemical/-fluorescence analysis demonstrated that maternal administration of RGZ shortly before birth stimulates epithelial and mesenchmal differentiation in nitrofen-induced PH compared to Placebo-treated foetuses, as evidenced by increased lamellar body count and ADRP expression. There was also a substantial accumulation of cytoplasmatic lipid droplets in alveolar interstitial cells, which was accompanied by a markedly increase of LIFs in the mesenchymal compartments of distal alveolar walls.
Taken together, these results suggest that RGZ has a therapeutic potential in attenuating foetal PH in rats with nitrofen-induced CDH through accelerating epithelial-mesenchymal interactions, which may result in enhanced expression of LIFs and thus alveolar maturation.
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Friedmacher FM. Effects of the peroxisome proliferator-activated receptor y agonist rosiglitazone on foetal lung development in an experimental rat model of congenital diaphragmatic hernia. [MSc Thesis]. Dublin: Royal College of Surgeons in Ireland; 2014.