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Epithelial cell PPAR contributes to normal lung maturation

Dawn M. Simon, Meltem C. Arikan^*, Sorachai Srisuma^,, Soumyaroop Bhattacharya^*, Larry W. Tsai^*, Edward P. Ingenito^*, Frank Gonzalez, Steven D. Shapiro^* and Thomas J. Mariani^*,1

^* Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;

Division of Respiratory Diseases, Children’s Hospital, Harvard Medical School, Massachusetts, USA;

Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; and

Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland, USA

¹Correspondence: Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Thorn 908, 75 Francis St., Boston, MA 02115, USA. tmariani@rics.bwh.harvard.edu

ABSTRACT

Peroxisome proliferator-activated receptor (PPAR)- is a member of the nuclear hormone receptor superfamily that can promote cellular differentiation and organ development. PPAR expression has been reported in a number of pulmonary cell types, including inflammatory, mesenchymal, and epithelial cells. We find that PPAR is prominently expressed in the airway epithelium in the mouse lung. In an effort to define the physiological role of PPAR within the lung, we have ablated PPAR using a novel line of mice capable of specifically targeting the airway epithelium. Airway epithelial cell PPAR-targeted mice display enlarged airspaces resulting from insufficient postnatal lung maturation. The increase in airspace size is accompanied by alterations in lung physiology, including increased lung volumes and decreased tissue resistance. Genome-wide expression profiling reveals a reduction in structural extracellular matrix (ECM) gene expression in conditionally targeted mice, suggesting a disruption in epithelial-mesenchymal interactions necessary for the establishment of normal lung structure. Expression profiling of airway epithelial cells isolated from conditionally targeted mice indicates PPAR regulates genes encoding known PPAR targets, additional lipid metabolism enzymes, and markers of cellular differentiation. These data reveal airway epithelial cell PPAR is necessary for normal lung structure and function.—Simon, D. M., Arikan, M. C., Srisuma, S., Bhattacharya, S., Tsai, L. W., Ingenito, E. P., Gonzalez, F., Shapiro, S. D., and Mariani, T. J. Epithelial cell PPAR contributes to normal lung maturation.

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