Modulation of airway remodeling and airway inflammation by peroxisome proliferator-activated receptor γ 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 (PPAR gamma) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPAR gamma in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPAR gamma agonist, rosiglitazone, or pioglitazone, and PPAR gamma 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-beta 1, and NF-kappa B 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 PPAR gamma agonists or adenovirus carrying PPAR gamma 2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-beta 1, and NF-kappa B in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-kappa B activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-beta 1 after TDI inhalation. These findings demonstrate a protective role of PPAR gamma in the pathogenesis of the TDI-induced asthma phenotype.