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Epithelial Cell PPAR Is an Endogenous Regulator of Normal Lung Maturation and Maintenance

Division of Pulmonary Medicine, Brigham and Women's Hospital, and Division of Respiratory Diseases, Children's Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Thomas J. Mariani, Ph.D., Pulmonary Medicine, Brigham and Women's Hospital, The Lung Biology Center, Harvard Medical School. E-mail: tmariani{at}partners.org

Peroxisome proliferator-activated receptor- (PPAR) is a nuclear hormone receptor that regulates gene expression, cellular differentiation, and tissue inflammation. PPAR is expressed in the murine lung in a spatio-temporally restricted pattern and is prominent within the airway epithelium. To study the physiologic role of this transcription factor in regulating lung development and the response to inflammatory stimuli, we have generated mice with conditional PPAR deficiency within the conducting airway epithelium. Isolated airway epithelial cells from conditionally targeted mice showed a 75% reduction in PPAR mRNA expression by real-time polymerase chain reaction and a 50% reduction in PPAR–expressing cells by immunocytochemistry. These mice display airspace enlargement in the absence of overt inflammation. Morphometric analysis revealed a 13% increase in chord length and 33% increase in airspace area (both p < 0.01) in targeted animals compared with littermate controls at 8 wk of age. There was no overt evidence of inflammation present. Abnormal airspaces were not present at 2 wk of age and persisted, but did not progress, at 9 mo of age. These data suggest a defect in terminal lung maturation, which occurs throughout the first month of life in rodents. Whole lung genomewide expression profiling revealed a general decrease in extracellular matrix (ECM) gene expression, including elastin and type I collagen. As these proteins are not expressed by the targeted epithelial cells, the data suggest a molecular mechanism for the observed phenotype whereby PPAR deficiency disrupts epithelial–mesenchymal interactions, resulting in decreased structural ECM gene expression and abnormal lung structure. Expression profiling of freshly isolated airway epithelial cells identified dysregulation of genes involved in PPAR function, lipid metabolism, cellular differentiation, and inflammation in the conditionally targeted animals. To examine the role of epithelial cell PPAR in regulating lung inflammation, we challenged adult mice to cigarette smoke for 6 mo. Targeted animals had greater smoke-induced emphysema when compared with age-matched, wild-type littermate controls (28% increase in chord length, 50% increase in alveolar area) and age-matched, unchallenged knockouts (20% increase in chord length, 29% increase in alveolar area). Targeted mice also showed an approximate twofold increase in macrophages number (p < 0.01) after smoke exposure, as quantified by MAC3 immunohistochemistry. We conclude that epithelial PPAR is necessary for proper lung maturation and response to injury. Ongoing studies are further defining the regulatory mechanisms involved.

ACKNOWLEDGMENTS

The authors thank Frank J. Gonzalez for providing the PPAR floxed mouse.

FOOTNOTES

Supported by the American Lung Association, the Francis Families Foundation, and the Cystic Fibrosis Foundation.

Conflict of Interest Statement: D.M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.C.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.D.S. has, in the past 3 yr, participated in advisory boards for Boehringer Ingelheim, GlaxoSmithKline, Millenium, Pfizer, Wyeth, and ICOS. His laboratory has performed research in collaboration with Pfizer, Arriva, ONO, and Taisho. Advisory board activity did not exceed $10,000/yr per company. No personal income was obtained from research grants. He receives a fixed stipend as Editor of the AJRCMB. T.J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form March 16, 2006; accepted in final form March 20, 2006)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Simon, D. M. Articles by Mariani, T. J. Search for Related Content PubMed PubMed Citation Articles by Simon, D. M. Articles by Mariani, T. J.