Background We have recently determined that disruption of pulmonary alveolar epithelial-mesenchymal paracrine loop, dictated by Peroxisome Proliferator Activated Receptor γ (PPARγ) expression by lung fibroblasts is a critical event in the pathobiology of bronchopulmonary dysplasia (BPD). In this study, we utilize a PPARγ ligand to reinforce the epithelial-mesenchymal paracrine loop to prevent lung injury in response to short-term hyperoxic ventilation in the developing rat.
Objective To determine if stabilization of epithelial-mesenchymal paracrine loop by PPARγ ligand, rosiglitazone (RGZ), prevents hyperoxia-induced alveolar lung injury in a ventilated developing rat model.
Design/Methods Two week old rat pups were anesthetized, and ventilated for 4h with 21% O2 (+ placebo), 95% O2 (+ placebo), or 95% O2 + 3 mg/kg RGZ in 100 μl i.p. administered 24h prior to ventilation. Peak Inspiratory/Positive End Expiratory Pressures were kept at 12/3 cm of water, and ventilatory rate was adjusted to keep PaCO2 (35-45 mm of Hg) similar among groups. At the end of 4h, bronchoalveolar lavage (BAL) was collected for Parathyroid Hormone-related Protein (PTHrP) determination using radioimmunoassay, animals sacrificed, and lung tissue analyzed for mRNA (RT-PCR) and protein (Western blotting) for alveolar type II cell [surfactant protein-B (SP-B), PTHrP, and leptin receptor], and fibroblast lipogenic [PTHrP receptor, PPARγ, and Adipocyte Differentiation Related Protein (ADRP), and leptin], and fibroblast myogenic [αsmooth muscle actin (αSMA)] markers.
Results Hyperoxic ventilation alone decreased PTHrP in BAL (p ≤0.05), decreased PTHrP, PTHrP receptor, SP-B, leptin, leptin receptor, PPARγ, and ADRP mRNA expression (p≤0.05 for all), while increasing the expression αSMA mRNA (p≤0.05). These changes were completely prevented by prior administration of RGZ. Similarly, significant decreases in some but not all alveolar type II and fibroblast lipogenic proteins in response to hyperoxia were prevented by RGZ.
Conclusions Our data provide clear evidence that PPARγ agonists can prevent hyperoxia-induced molecular lung injury that is known to lead to BPD. This is the first demonstration that reinforcing critically important epithelial-mesenchymal signaling pathways through the manipulation of the nuclear transcription factor, PPARγ, may be a novel and effective approach to prevent BPD.
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