The physiological development and homeostasis of the lung alveolus is determined by the expression of peroxisome proliferator-activated receptor-␥ (PPAR-␥) 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-␥ 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-␥ 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% O 2 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-␣, leptin receptor, triglyceride uptake, and [ 3 H]choline incorporation into saturated phosphatidylcholine) and injury/repair, in particular, the markers of transforming growth factor-␤ 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-␤ intermediates, such as SMAD3 and lymphoid enhancer factor-1, implicated in hyperoxic lung injury, was also blocked by antenatal RGZ treatment. In conclusion, PPAR-␥ agonists can enhance fetal lung maturation and can effectively prevent hyperoxia-induced neonatal lung injury. lung development; peroxisome proliferator-activated receptor-␥; surfactant; lipofibroblast; hyperoxia SEVERAL LINES OF EVIDENCE suggest that lipids are cytoprotective against oxygen free radical lung injury in vitro and in vivo (5,23,37). Investigators have suggested that the greater oxygen tolerance of newborn rats and mice, compared with their adult counterparts, relates, in part, to the greater amount of triglyceride in the lipid fraction of the newborn compared with the adult lung (14,24,25,37). Feeding pregnant rats a high triglyceride diet results in increased triglyceride content in the lungs of their offspring, increased survival, and improved pathological status after prolonged hyperoxic exposure (25). In contrast, newborn offspring of rats fed low-polyunsaturated fatty acid diets are more susceptible to pulmonary oxygen toxicity and early lethality in hyperoxia (24). Furthermore, Kehrer and Autor (14) demonstrated that increasing the saturated fatty acid composition of lung triglycerides in adult rats by dietary manipulation produced increased susceptibility to oxygen toxicity.Ou...

Maternal food restriction (MFR) during pregnancy affects pulmonary surfactant production in the intrauterine growth-restricted (IUGR) offspring through unknown mechanisms. Since pulmonary surfactant production is regulated by maternal and fetal corticosteroid levels, both known to be increased in IUGR pregnancies, we hypothesized that metyrapone (MTP), a glucocorticoid synthesis inhibitor, would block the effects of MFR on surfactant production in the offspring. Three groups of pregnant rat dams were used (1) control dams fed ad libitum; (2) MFR (50% reduction in calories) from days 10 to 22 of gestation; and (3) MFR þ MTP in drinking water (0.5 mg/mL), days 11 to 22 of gestation. At 5 months, the MFR offspring weighed significantly more, had reduced alveolar number, increased septal thickness, and decreased surfactant protein and phospholipid synthesis. These MFR-induced effects were normalized by the antiglucocorticoid MTP, suggesting that the stress of MFR causes hypercorticoidism, altering lung structure and function in adulthood.