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341 THE SAFETY AND EFFICACY OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR γ AGONIST ROSIGLITAZONE FOR LUNG DIFFERENTIATION IN A NEONATAL RAT MODEL.
  1. H. Sindalana1,
  2. Y. Wang1,
  3. R. Sakurai1,
  4. L. Cerny1,
  5. J. S. Torday1,
  6. V. K. Rehan1
  1. 1Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.

Abstract

Background Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the retinoid X-receptor heterodimer family of ligand-activated nuclear receptors, plays a critical role in modulating lung injury/repair. Recently, using both in vitro and in vivo models of acute neonatal lung injury, our laboratory has shown that PPAR-γ agonists can prevent nicotine- and short-term hyperoxia-induced lung injury. These studies clearly suggest the potential therapeutic usefulness of PPAR-γ agonists in preventing neonatal lung injury. However, there is no information on the effects of systemically administered PPAR-γ agonists on lung differentiation and metabolic profile in the developing system.

Objectives To determine the effects of systemically administered PPAR-γ agonist rosiglitazone (RGZ) on lung differentiation, serum electrolytes, blood glucose, and blood gases in a developing neonatal rat model.

Methods Newborn Sprague-Dawley rat pups were divided into the following six groups: control and RGZ 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 8 mg/kg groups. The diluent (saline) or RGZ was administered IP in 100 μL volumes once daily for either 1 day or 7 days. The pups were sacrificed and the lungs were collected and processed either immediately for choline incorporation and triolein uptake or later for protein (Western hybridization) and mRNA (RT-PCR) analysis for markers of lung maturation.

Results Systemically administered RGZ significantly increased the expression of surfactant proteins B and C, cholinephosphate cytidyltransferase, PPAR-γ, and adipocyte differentiation-related protein in a dose-dependent manner, both at day 1 and day 7. This was also accompanied by significantly increased choline incorporation and triolein uptake, the functional markers of surfactant phospholipid synthesis. There were no significant effects on serum electrolytes, blood glucose, and blood gases except at the highest dose of RGZ (8 mg/kg), which resulted in significantly lower blood glucose values.

Conclusions Systemically administered RGZ significantly enhances lung differentiation without significantly affecting the serum metabolic profile. We speculate that PPAR-γ agonists may be safe and effective agents for enhancing repair of lung injury in neonates.

Supported by grants from NIH (HL55268 and HL075405), TRDRP (14RT-0073 and 15IT-0250), and Philip Morris USA Inc. and Philip Morris International.

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