Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, prevents hyperoxia-induced neonatal rat lung injury in vivo.
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 (PPARgamma) (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 PPARgamma agonists may be a novel, effective strategy to prevent the hyperoxia-induced lung molecular injury that has been implicated in the pathogenesis of BPD.
Rehan
Virender K
VK
Department of Pediatrics, Los Angeles Biomedical Research Center at Harbor UCLA, David Geffen UCLA School of Medicine, University of California at Los Angeles, Torrance, California 90502, USA. vrehan@labiomed.org
Wang
Ying
Y
Patel
Sanjay
S
Santos
Jamie
J
Torday
John S
JS
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology / Q000517:prevention & control*; D055370:Lung Injury; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000070780:Perilipin-2; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D000199:Actins; D000813:Anilides; D008565:Membrane Proteins; D047495:PPAR gamma; D000070780:Perilipin-2; D037701:Pulmonary Surfactant-Associated Protein B; D000077154:Rosiglitazone; D045162:Thiazolidinediones; C457499:2-chloro-5-nitrobenzanilide; C498862:Acta2 protein, rat