title: Airway epithelial cell PPARγ modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice.
abstract: Chronic obstructive pulmonary disease (COPD) is a highly prevalent, chronic inflammatory lung disease with limited existing therapeutic options. While modulation of peroxisome proliferator-activating receptor (PPAR)-γ activity can modify inflammatory responses in several models of lung injury, the relevance of the PPARG pathway in COPD pathogenesis has not been previously explored. Mice lacking Pparg specifically in airway epithelial cells displayed increased susceptibility to chronic cigarette smoke (CS)-induced emphysema, with excessive macrophage accumulation associated with increased expression of chemokines, Ccl5, Cxcl10, and Cxcl15. Conversely, treatment of mice with a pharmacological PPARγ activator attenuated Cxcl10 and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPARγ activation-dependent fashion. The ability of PPARγ to regulate CS-induced chemokine expression in vitro was not specifically associated with peroxisome proliferator response element (PPRE)-mediated transactivation activity but was correlated with PPARγ-mediated transrepression of NF-κB activity. Pharmacological or genetic activation of PPARγ activity abrogated CS-dependent induction of NF-κB activity. Regulation of NF-κB activity involved direct PPARγ-NF-κB interaction and PPARγ-mediated effects on IKK activation, IκBα degradation, and nuclear translocation of p65. Our data indicate that PPARG represents a disease-relevant pathophysiological and pharmacological target in COPD. Its activation state likely contributes to NF-κB-dependent, CS-induced chemokine-mediated regulation of inflammatory cell accumulation.
authors.affiliation: Division of Neonatology and Pediatric Molecular and Personalized Medicine Program, University of Rochester Medical Center, Rochester, New York;
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Solleti
authors.affiliation: Emory-Children's Center Pulmonary, Apnea, Cystic Fibrosis and Sleep Clinic, Atlanta, Georgia;
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Simon
authors.affiliation: Faculty of Medicine, Department of Physiology, Siriraj Hospital, Mahidol University, Bangkok, Thailand;
authors.forename: Sorachai
authors.initials: S
authors.lastname: Srisuma
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Meltem C
authors.initials: MC
authors.lastname: Arikan
authors.affiliation: Division of Neonatology and Pediatric Molecular and Personalized Medicine Program, University of Rochester Medical Center, Rochester, New York; Tom_Mariani@urmc.rochester.edu.
authors.forename: Soumyaroop
authors.identifier: http://orcid.org/0000-0003-1140-7845
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of Rochester Medical Center, Rochester, New York;
authors.forename: Tirumalai
authors.initials: T
authors.lastname: Rangasamy
authors.affiliation: Division of Neonatology and Pediatric Molecular and Personalized Medicine Program, University of Rochester Medical Center, Rochester, New York; Atlanta VA and Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University, Atlanta, Georgia;
authors.forename: Kaiser M
authors.initials: KM
authors.lastname: Bijli
authors.affiliation: Division of Neonatology and Pediatric Molecular and Personalized Medicine Program, University of Rochester Medical Center, Rochester, New York;
authors.forename: Arshad
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado;
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Crossno
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.affiliation: Division of Neonatology and Pediatric Molecular and Personalized Medicine Program, University of Rochester Medical Center, Rochester, New York; Tom_Mariani@urmc.rochester.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
mesh_terms: D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism*; D004198:Disease Susceptibility; D005260:Female; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000502:physiology*; D011656:Pulmonary Emphysema / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018925:Chemokines; D016328:NF-kappa B; D047495:PPAR gamma
keywords: chronic obstructive pulmonary disease; lung inflammation; nuclear factor-kB; peroxisome proliferator-activating receptor-γ; rosiglitazone