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

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) plays an important role in lipid and glucose metabolism. In this study, the function of PPARγ on lung development was investigated. Lung-specific Pparg conditional knockout mice (PpargΔLuEpC) were developed using Cre-Lox system. PpargΔLuEpC 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 Pmaip1, 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 PpargΔLuEpC mice. In addition, expression of Pthlh, a gene pheno-typically expressed in the congenital cystic adenomatoid malformation (CCAM), was increased at E14.5 to E18.5 in the lung of PpargΔLuEpC mice. Cell culture studies revealed that PPARγ 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 PpargΔLuEpC 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 Cdh1, a gene related to cell adhesion, was significantly reduced in the MLE-15-shPparg cells. Taken together, PPARγ may play an important role in fetal lung development via alveolar cell-to-cell adhesion system.

Developmental Timing Determines the Protective Effect of Maternal Electroacupuncture on Perinatal Nicotine Exposure-Induced Offspring Lung Phenotype

“…Mammalian lung morphogenesis is a complex, finely orchestrated program, which progresses through well defined, sequential stages to result in fully functional lung; for example, the rat lung development proceeds through the embryonic (E11-13), pseudoglandular (E13-18.5), canalicular (E18. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], saccular (E20-PND4), and alveolar (PND4-21) stages. Specific growth factors and signaling mechanisms regulate each stage and drive its progression to the next stage [54].…”

“…Nicotine's effects on the developing lung have been largely attributed to a disruption in epithelial-mesenchymal paracrine signaling, the central component of which is the nuclear transcription factor peroxisome proliferator-activated receptor-c (PPARc). PPARc is centrally involved in alveolar and airway development [18][19][20] and is a key determinant of the alveolar fibroblast differentiation to lipofibroblasts, which are essential for alveolar development, homeostasis, and injury repair [18,21]. Lung-specific PPARc knockout mice show enlarged alveolar sacs, increased apoptotic cells, and an enlarged lung volume, highlighting PPARc's indispensable role in lung development [19,20].…”

“…PPARc is centrally involved in alveolar and airway development [18][19][20] and is a key determinant of the alveolar fibroblast differentiation to lipofibroblasts, which are essential for alveolar development, homeostasis, and injury repair [18,21]. Lung-specific PPARc knockout mice show enlarged alveolar sacs, increased apoptotic cells, and an enlarged lung volume, highlighting PPARc's indispensable role in lung development [19,20]. Nicotine, by down-regulating PPARc, drives alveolar lipofibroblasts to transdifferentiate to myofibroblasts, which are the hallmarks of all chronic lung conditions including the perinatal nicotine exposure-(PNE-) induced lung damage [22,23].…”

PER2-mediated ameloblast differentiation via PPARγ/AKT1/β-catenin axis

“…PPARγ, a transcription factor of the ligand-activated nuclear receptor superfamily, plays an essential role in pulp cell survival, pulp homeostasis and dentin mineralization. 33 , 34 Moreover, PPARγ is expressed in type II alveolar epithelial cells and is necessary for lung development, 35 which indicates the involvement of PPARγ in epithelial cell differentiation. However, the role of PPARγ in ameloblasts, the most important epithelium-derived cell in enamel formation, remains unclear.…”

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

“…A role for PPAR-␥ signaling has also been explored in developing fetal lungs, where the gene encoding PPAR-␥ (Pparg) was deleted in the developing lung epithelium using an Sftpc-Cre line (267). Fetal lungs exhibited increased alveoli size, accompanied by increased expression of Pthlh, encoding parathyroid hormone-like peptide, which exhibits increased expression in congenital cystic adenomatoid malformation (CCAM).…”