Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, prevents hyperoxia-induced neonatal rat lung injury in vivo

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Abstract
Molecular disruption of homeostatic alveolar epithelial‐mesenchymal interactions results in transdifferentiation of alveolar interstitial lipofibroblasts to myofibroblasts. Although this process was suggested to be a central molecular event in the pathogenesis of bronchopulmonary dysplasia (BPD), so far it has been only demonstrated in vitro; whether it also occurs in vivo is unknown. Our objectives were to determine if exposure to hyperoxia results in pulmonary alveolar lipo‐to‐myofibroblast transdifferentiation in vivo, and whether treatment with a potent peroxisome proliferator‐activated receptor gamma (PPARγ) (the key lipogenic fibroblast nuclear transcription factor) agonist, rosiglitazone, prevents this process. Newborn Sprague Dawley rat pups were exposed to control (21% O2), hyperoxia alone (95% O2 for 24 hr), or hyperoxia with rosiglitazone (95% O2 for 24 hr + rosiglitazone, 3 mg/kg, administered intraperitoneally) conditions. Subsequently, pups were sacrificed, and lung tissue was analyzed by morphometry, and by reverse transcription‐polymerase chain reaction, Western hybridization, and immunohistochemistry for the expression of key lipogenic and myogenic markers. We observed a significant decrease in the expression of lipogenic markers, and a significant increase in the expression of myogenic markers in the hyperoxia‐alone group. These hyperoxia‐induced morphologic, molecular, and immunohistochemical changes were almost completely prevented by rosiglitazone. This is the first evidence of in vivo lipo‐to‐myofibroblast transdifferentiation and its almost complete prevention by rosiglitazone, prompting us to conclude that administration of PPARγ agonists may be a novel, effective strategy to prevent the hyperoxia‐induced lung molecular injury that has been implicated in the pathogenesis of BPD. Pediatr Pulmonol.