Modulation of airway remodeling and airway inflammation by peroxisome proliferator-activated receptor gamma in a murine model of toluene diisocyanate-induced asthma.
Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling. Peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPARgamma in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPARgamma agonist, rosiglitazone, or pioglitazone, and PPARgamma on TDI-induced bronchial inflammation and airway remodeling. This study with the TDI-induced model of asthma revealed the following typical pathophysiological features: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased levels of Th2 cytokines (IL-4, IL-5, and IL-13), adhesion molecules (ICAM-1 and VCAM-1), chemokines (RANTES and eotaxin), TGF-beta1, and NF-kappaB in nuclear protein extracts. In addition, the mice exposed to TDI developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer, subepithelial collagen deposition, and increased airway mucus production. Administration of PPARgamma agonists or adenovirus carrying PPARgamma2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-beta1, and NF-kappaB in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-kappaB activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-beta1 after TDI inhalation. These findings demonstrate a protective role of PPARgamma in the pathogenesis of the TDI-induced asthma phenotype.
Lee
Kyung Sun
KS
Department of Internal Medicine, Airway Remodeling Laboratory, Chonbuk National University Medical School, Jeonju, South Korea. leeyc@chonbuk.ac.kr
Park
Seoung Ju
SJ
Kim
So Ri
SR
Min
Kyung Hoon
KH
Jin
Sun Mi
SM
Lee
Hern Ku
HK
Lee
Yong Chul
YC
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000032:analysis; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D012137:Respiratory System / Q000473:pathology*; D018418:Th2 Cells; D014051:Toluene 2,4-Diisocyanate / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000032:analysis
D015815:Cell Adhesion Molecules; D016207:Cytokines; D016328:NF-kappa B; D047495:PPAR gamma; D053773:Transforming Growth Factor beta1; D014051:Toluene 2,4-Diisocyanate