Antenatally administered PPAR-γ agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury

Author:

Rehan Virender K.1,Sakurai Reiko1,Corral Julia1,Krebs Melissa1,Ibe Basil1,Ihida-Stansbury Kaori2,Torday John S.1

Affiliation:

1. Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance, California; and

2. the 2Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania

Abstract

The physiological development and homeostasis of the lung alveolus is determined by the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) by the interstitial lipofibroblast. We have recently shown (Dasgupta C et al., Am J Physiol Lung Cell Mol Physiol 296: L1031–L1041, 2009.) that PPAR-γ agonists administered postnatally accelerate lung maturation and prevent hyperoxia-induced lung injury. However, whether the same occurs antenatally is not known. The objective of this study was to test the hypothesis that the potent PPAR-γ agonist rosiglitazone (RGZ), administered antenatally, enhances fetal lung maturation and protects against hyperoxia-induced neonatal lung injury. Sprague-Dawley rat dams were administered either diluent or RGZ (3 mg/kg), at late gestation, to determine its effect on lung maturation and on hyperoxia (95% O2 exposure for 24 h)-induced neonatal lung injury. The lungs were examined for the expression of specific markers of alveolar development (surfactant proteins A and B, cholinephosphate cytidylyltransferase-α, leptin receptor, triglyceride uptake, and [3H]choline incorporation into saturated phosphatidylcholine) and injury/repair, in particular, the markers of transforming growth factor-β signaling (activin receptor-like kinase-5, SMAD3, lymphoid enhancer factor-1, fibronectin, and calponin). Overall, antenatal RGZ accelerated lung maturation and blocked the inhibition of alveolar sacculation and septal wall thinning by hyperoxia. RGZ specifically stimulated the development of the alveolar epithelial type II cell, the lipofibroblast, and the vasculature. The increased expression of the transforming growth factor-β intermediates, such as SMAD3 and lymphoid enhancer factor-1, implicated in hyperoxic lung injury, was also blocked by antenatal RGZ treatment. In conclusion, PPAR-γ agonists can enhance fetal lung maturation and can effectively prevent hyperoxia-induced neonatal lung injury.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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