Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 309, Issue 3, Pages L293-L304Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00287.2014
Keywords
lung inflammation; chronic obstructive pulmonary disease; rosiglitazone; nuclear factor-kB; peroxisome proliferator-activating receptor-gamma
Categories
Funding
- National Heart, Lung, and Blood Institute [HL-094431]
- Flight Attendant Medical Research Institute
- American Lung Association
- Francis Families Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL094431] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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)-gamma 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 PPAR gamma activator attenuated Cxcl10 and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPAR gamma activation-dependent fashion. The ability of PPAR gamma 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 PPAR gamma -mediated transrepression of NF-kappa B activity. Pharmacological or genetic activation of PPAR gamma activity abrogated CS-dependent induction of NF-kappa B activity. Regulation of NF-kappa B activity involved direct PPAR gamma-NF-kappa B interaction and PPAR gamma-mediated effects on IKK activation, I kappa B alpha 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-kappa B-dependent, CS-induced chemokine-mediated regulation of inflammatory cell accumulation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available