Agonistic Induction of PPARgamma Reverses Cigarette Smoke-Induced Emphysema

Details

• Personal Author:
  Corry DB ; Frazier MV ; Hilsenbeck S ; Hong J-S ; Kheradmand F ; Perusich S ; Porter P ; Seryshev A ; Shan M ; Song L-z ; Whitehead L ; You R ; Yuan X ; Zarinkamar N ; Zhang Y
• Description:
  The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator-activated receptor gamma (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARgamma in APCs using Cd11c-Cre Pparg(flox/flox) mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg(flox/flox) mice required OPN, suggesting an antiinflammatory mechanism in which PPARgamma negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARgamma agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARgamma agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARgamma activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema. [Description provided by NIOSH]
• Subjects:
  Drug Therapy Immune System Lung Diseases Occupational Health Pathology Respiratory Tract Diseases Safety Smokers Tobacco Products
• Keywords:
  Autoimmune Diseases Cigarette Smoke Cigarette Smoking Cytokines Drug Therapy Etiology Gene Expression Immune Reaction Lung Disease Myeloid Tissue Proteins

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• ISSN:
  0021-9738
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 6 ; Texas
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  124
• Issue:
  3
• NIOSHTIC Number:
  nn:20064584
• Citation:
  J Clin Invest 2014 Mar; 124(3):1371-1381
• Contact Point Address:
  Farrah Kheradmand or David B. Corry, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza Suite M915B, Houston, Texas 77030, USA
• Email:
  farrahk@bcm.edu
• Federal Fiscal Year:
  2014
• Performing Organization:
  University of Texas Health Science Center, Houston
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Journal of Clinical Investigation
• End Date:
  20250630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:ce0bc946b5c61c8dba43d54d0ca567703b52dcccf5d13d798722ca48cc59b5887edecb2cdfbaa3d02f31f2eacf2330ae9bbdcdffe01e8a933311f70a41800bd0
• Download URL:
  https://stacks.cdc.gov/view/cdc/223021/cdc_223021_DS1.pdf
• File Type:
  [PDF - 1.92 MB ]