Epithelial cell PPARγ contributes to normal lung maturation

Abstract

Peroxisome proliferator-activated receptor (PPAR)-gamma is a member of the nuclear hormone receptor superfamily that can promote cellular differentiation and organ development. PPARgamma expression has been reported in a number of pulmonary cell types, including inflammatory, mesenchymal, and epithelial cells. We find that PPARgamma is prominently expressed in the airway epithelium in the mouse lung. In an effort to define the physiological role of PPARgamma within the lung, we have ablated PPARgamma using a novel line of mice capable of specifically targeting the airway epithelium. Airway epithelial cell PPARgamma-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 PPARgamma regulates genes encoding known PPARgamma targets, additional lipid metabolism enzymes, and markers of cellular differentiation. These data reveal airway epithelial cell PPARgamma is necessary for normal lung structure and function.

Characterization of the cell of origin for small cell lung cancer

“…28,29 The same conditional allele of p53 and a different conditional allele of Rb 48 were bred together and crossed to Scgb1a1-Cre mice. [19][20][21] The two reporter mouse strains used, Rosa26R and Rosa26 LSL-YFP/+ , have been extensively described in reference 23 and 26. Doxycycline was administered in the drinking water at 1 mg/ml for one month as previously described in references 28 and 29.…”

“…Because most of the SCLC lesions are found in bronchioles and terminal bronchioles, which are composed in majority of Clara cells, we crossed Rb lox/lox ;p53 loxlox mice to Scgb1a1-Cre mice. [19][20][21] Scgb1a1 codes for the Clara cell-specific protein (CCSP, also known as CCA or CC10), which marks Clara cells throughout the distal bronchiolar epithelium as well as BASCs at the BADJ 15,22 and Cre expression in the Scgb1a1-Cre strain, has been shown to be limited to the bronchiolar epithelium. [19][20][21] To confirm these previous reports, we crossed Scgb1a1-Cre mice to Rosa26 lox-stop-lox-LacZ (Rosa26R) reporter mice, where lacZ expression is induced after Cre-mediated recombination, 23 and detected lacZ activity by X-gal staining in the bronchiolar epithelium but not in neuroendocrine cells, as expected (Fig.…”

Airway Lipoxin A4Generation and Lipoxin A4Receptor Expression Are Decreased in Severe Asthma

“…GenBank accession numbers for 5-LO, 15-LO-1, 15-LO-2, COX-2, and ALX are J03600.1, M23892.1, U78294.1, M90100.1, and M84562.1, respectively. qPCR was performed with a Stratagene MX 3000P sequence detection system (Stratagene, La Jolla, CA), using fluorescent TaqMan methodology (Applied Biosystems) as described previously (27). Briefly, cyclophilin A was used as the control gene and quantitation was done by calculating the cycle threshold (C t The difference between the C t value for the gene of interest and the respective C t value for cyclophilin A was then calculated (DC t ).…”

Peroxisome Proliferator-Activated Receptor γ Agonist Down-Regulates IL-17 Expression in a Murine Model of Allergic Airway Inflammation

“…Among three PPAR subtypes, PPAR␥ activation down-regulates the synthesis and release of immunomodulatory cytokines from various cell types that participate in the regulation of inflammatory processes. In lung tissues, PPAR␥ is most abundant in airway epithelial cells (16). In addition, PPAR␥ is also expressed in smooth muscle cells, myofibroblasts, endothelial cells of the pulmonary vasculature, and inflammatory cells such as alveolar macrophages, neutrophils, eosinophils, lymphocytes, and mast cells (17,18).…”