Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways - Relationship with proliferation, apoptosis, and airway remodeling

Airway inflammation and alterations in cellular turnover are histopathologi c features of asthma. We show that the expression of peroxisome proliferato r-activated receptor gamma (PPAR gamma), a nuclear hormone receptor involve d in cell activation, differentiation, proliferation, and/or apoptosis, is augmented in the bronchial submucosa, the airway epithelium, and the smooth muscle of steroid-untreated asthmatics, as compared with control subjects. This is associated with enhanced proliferation and apoptosis of airway epi thelial and submucosal cells, as assessed by the immunodetection of the nuc lear antigen Ki67, and of the cleaved form of caspase-3, respectively, and with signs of airway remodeling, including thickness of the subepithelial m embrane (SBM) and collagen deposition. PPAR gamma expression in the epithel ium correlates positively with SBM thickening and collagen deposition, wher eas PPAR gamma expressing cells in the submucosa relate both to SBM thicken ing and to the number of proliferating cells. The intensity of PPAR gamma e xpression in the bronchial submucosa, the airway epithelium, and the smooth muscle is negatively related to FEV, values. Inhaled steroids alone, or as sociated with oral steroids, downregulate PPAR gamma expression in all the compartments, cell proliferation, SBM thickness, and collagen deposition, w hereas they increase apoptotic cell numbers in the epithelium and the submu cosa. Our findings have demonstrated that PPAR gamma (1) is a new indicator of airway inflammation and remodeling in asthma; (2) may be involved in ex tracellular matrix remodeling and submucosal cell proliferation; (3) is a t arget for steroid therapy.