Lack of epithelial PPARy causes cystic adenomatoid malformations in mouse fetal lung

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) plays an important role in lipid and glucose metabolism. In this study, the function of PPARy on lung development was investigated. Lung-specific, Pparg conditional knockout mice (Pparg(Delta LuEpC)) were developed using Cre-Lox system. Pparg(Delta LuEpC) mice showed abnormal lung development with enlarged airspaces and followed by increase of apoptotic cells at E14.5 to E18.5. Gene analysis revealed that expression of Pmaipl, a gene related to apoptosis, was significantly increased while expression of Retnla, a gene related to anti-apoptosis, was dramatically decreased in the fetal lung (E14.5) of Pparg(Delta LuEpC) mice. In addition, expression of Pthlh, a gene phenotypically expressed in the congenital cystic adenomatoid malformation (CCAM), was increased at E14.5 to E18.5 in the lung of Pparg(Delta LuEpCmice). Cell culture studies revealed that PPARy could bind to promoter region of Pthlh gene as a repressor in the immortalized mouse lung epithelial cell line MLE-15. Surprisingly, phenotypic changes in MLE-15-shPparg cells, stably transfected with shPparg plasmid, were similar to the pparg(Delta tuEpC) mice model. In addition, MLE-15-shPparg cells were easily detached from the cultured plate when cold phosphate buffered saline was applied. Furthermore, expression of Cdhl, a gene related to cell adhesion, was significantly reduced in the MLE-15-shPparg cells. Taken together, PPARy may play an important role in fetal lung development via alveolar cell-to-cell adhesion system. (C) 2017 Elsevier Inc. All rights reserved.