Abnormal injury/repair, with truncation of alveolarization, is the major histopathological hallmark of """"""""The New Bronchopulmonary Dysplasia (BPD)"""""""". We have recently proposed that disrupting normal homeostatic epithelial-mesenchymal communications, and the consequent alveolar interstitial fibroblast (AIF)-to-myofibroblast (MYF) transdifferentiation, are the key events in its pathobiology. The specific molecular mechanisms involved in this process remain incompletely defined. The objective of this proposal is to determine the specific molecular mechanisms involved in BPD, particularly the role of Peroxisome Proliferator Activated Receptor (PPAR) signaling in hyperoxia-induced rat lung AIF-to-MYF transdifferentiation, using both in vivo and in vitro models and to determine the effectiveness of a novel molecular preventive and therapeutic approach.
In Specific Aim 1, using Laser Capture Microdissection, Morphometry, Immunohistochemistry, Real Time-PCR, Northern, and Western analyses, we will determine, in an in vivo neonatal rat model, how PPAR agonists prevent and/or treat hyperoxia-induced AIF-to-MYF transdifferentiation.
In Specific Aim 2, using Real Time -PCR, Northern and Western analyses, Metabolomics, Antisense, and Transfection in vitro studies, for the mRNA expression of Parathyroid Hormone-related Protein Receptor, PPAR, C/Enhancer Binding Protein, and Adipocyte Differentiation Related Protein, coupled with the differential expression and phosphorylation of the corresponding proteins, we will determine the mechanism involved in AIF-to-MYF transdifferentiation. We will also determine how AIF-to-MYF transdifferentiation can be prevented or reversed by stimulating the lipogenic pathway through potent PPAR ligands such as rosiglitazone and GW7845. This proposal, in addition to providing new insights into the pathobiology of BPD, has enormous potential for opening up novel interventional strategies to tackle chronic lung disease in general, and BPD in particular. In fact, using the functional genomic approach, adopted in our proposal, i.e., inducing lipogenic transcription factors, may not only prevent, but may also reverse established chronic lung disease. The concept put forward in this proposal is novel, innovative, and departs from the traditional paradigm of oxygen-induced lung damage, and may have much wider implications than simply understanding oxygen-induced lung injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Blaisdell, Carol J
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La Biomed Research Institute/ Harbor UCLA Medical Center
United States
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Sakurai, Reiko; Lee, Cindy; Shen, Humphrey et al. (2018) A Combination of the Aerosolized PPAR-? Agonist Pioglitazone and a Synthetic Surfactant Protein B Peptide Mimic Prevents Hyperoxia-Induced Neonatal Lung Injury in Rats. Neonatology 113:296-304
Torday, John S; Rehan, Virender K (2016) On the evolution of the pulmonary alveolar lipofibroblast. Exp Cell Res 340:215-9
Paek, David S; Sakurai, Reiko; Saraswat, Aditi et al. (2015) Metyrapone alleviates deleterious effects of maternal food restriction on lung development and growth of rat offspring. Reprod Sci 22:207-22
Gong, M; Liu, J; Sakurai, R et al. (2015) Perinatal nicotine exposure suppresses PPAR? epigenetically in lung alveolar interstitial fibroblasts. Mol Genet Metab 114:604-12
Yurt, Methap; Liu, Jie; Sakurai, Reiko et al. (2014) Vitamin D supplementation blocks pulmonary structural and functional changes in a rat model of perinatal vitamin D deficiency. Am J Physiol Lung Cell Mol Physiol 307:L859-67
Morales, Edith; Sakurai, Reiko; Husain, Sumair et al. (2014) Nebulized PPAR? agonists: a novel approach to augment neonatal lung maturation and injury repair in rats. Pediatr Res 75:631-40
Rehan, Virender K; Li, Yishi; Corral, Julia et al. (2014) Metyrapone blocks maternal food restriction-induced changes in female rat offspring lung development. Reprod Sci 21:517-25
Rehan, Virender K; Torday, John S (2014) The lung alveolar lipofibroblast: an evolutionary strategy against neonatal hyperoxic lung injury. Antioxid Redox Signal 21:1893-904
Rehan, Virender K; Liu, Jie; Sakurai, Reiko et al. (2013) Perinatal nicotine-induced transgenerational asthma. Am J Physiol Lung Cell Mol Physiol 305:L501-7
Liu, Jie; Naeem, Erum; Tian, Jia et al. (2013) Sex-specific perinatal nicotine-induced asthma in rat offspring. Am J Respir Cell Mol Biol 48:53-62

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