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.