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

Abstract

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...

Functional assessment of hyperoxia-induced lung injury after preterm birth in the rabbit

“…These results parallel those observed in other hyperoxic lung injury animal models (2,6,24,27,32) as well as what is clinically observed (16). These changes represent a lung developmental arrest, typically characterized by a simplification with enlarged alveoli and thickened septa (6,24,27,32).…”

“…Because those large animal models are also associated with ethical and financial constraints, many researchers resort to smaller alternatives. Excellent research into BPD has already been performed in rodent models (2,9,14,15,24,25,27,36). Unfortunately, their lung development differs from humans since birth occurs in the early saccular stage of lung development and alveolarization only starts several days later.…”

Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

“…Second, whereas the earlier-appearing lipofibroblast population was shown to be important in surfactant production in vitro (40, 41), Thy-1 2/2 mouse pups do not exhibit respiratory distress or lung histology consistent with surfactant deficiency (10,25,42). The prevention of lipofibroblast-to-myofibroblast differentiation by the prenatal administration of rosiglitazone increased the numbers of lamellar bodies in alveolar Type II cells in rats on PND1 (43), supporting the assertion that earlier-appearing lipofibroblasts may play a role in surfactant production, but the later-appearing Thy-1 (1) lipofibroblasts do ;not.…”

Curcumin augments lung maturation, preventing neonatal lung injury by inhibiting TGF-β signaling

“…Curcumin was found to stimulate the key genes necessary for lipofibroblast differentiation (22), which protects the lung against oxidant injury (35). Furthermore, oxidant injury, which downregulates these genes, was inhibited by curcumin treatment in vitro and in vivo, thereby preserving the molecular and structural integrity of the alveoli.…”

“…Confocal immunofluorescent analysis for Smad3 (green; catalog no. C67H9, Cell Signaling) and nuclei (blue; TO-Pro-3 Iodide, Invitrogen) was performed as described previously (22). For tissue immunofluorescence staining for the relevant proteins, rat lungs were inflated in situ with 4% paraformaldehyde in phosphate buffer at a standard inflation pressure of 5 cmH 2O for 4 h at 4°C.…”