Activation of peroxisome proliferator-activated receptor gamma supresses inducible cyclooxygenase and nitric oxide synthase during oral mucosal ulcer healing

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-dependent transcription factor, belonging to the steroid hormone receptor family, known to play a pivotal role in the resolution of inflammation. In this study, we investigated the effect of a specific PPARgamma ligand, ciglitazone, on the course of buccal mucosal ulcer healing by analyzing mucosal activity of inducible nitric oxide synthase (NOS-2) and the expression cyclooxygenases (COX-1 and COX-2) responsible for prostaglandin (PG) generation. Methods: Groups of rats with experimentally induced buccal mucosal ulcers were administered twice daily for up to 10 days with ciglitazone at 5, 10, and 15 mg/kg or the vehicle, and their mucosal tissue subjected to assessment of ulcer healing rate and biochemical measurements. Results: The ulcer onset, characterized by up-regulation of NOS-2 and COX-2 protein expression, was reflected in a marked increase in the mucosal PGE2 generation and NOS-2 activity, whereas healing was accompanied by a drop in PGE2 and NOS-2 activity, and a decrease in COX-2 and NOS-2 protein expression. The mucosal expression of COX-1 protein, however, remained unchanged. Administration of ciglitazone led to a significant dose-dependent acceleration in the mucosal reduction of PGE2 generation and NOS-2 activity, and produced a marked decline in COX-2 and NOS-2 protein expression, but the rate of ulcer healing and the expression of COX-1 protein remained unaffected. Conclusions: Our findings thus suggest that the products of induced NOS-2 and COX-2 enzymes, associated with mucosal inflammatory responses to injury, do not play a significant role in oral mucosal ulcer healing.