Role of peroxisome proliferator-activated receptor γ activation in gastric mucosal ulcer healing

Peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ ligand, ciglitazone, on the course of gastric ulcer healing by analyzing apoptotic processes and the mucosal activity of inducible nitric oxide synthase (NOS-2), and the expression cyclooxygenases (COX-1 and COX-2) responsible for prostaglandin (PG) generation. Groups of rats with experimentally induced gastric mucosal ulcers were administered twice daily for up to 14 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. The ulcer onset, characterized by a massive epithelial apoptosis and 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 decrease in apoptosis, 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, epithelial cell apoptosis and NOS-2 activity, and produced a marked decline in COX-2 and NOS-2 protein expression, but the rate of ulcer healing remained unaffected. Our findings with PPARγ activator, ciglitazone, thus provide evidence that the products of induced expression of NOS-2 and COX-2 enzymes, associated with the ulcer onset, do not play a significant role in gastric ulcer healing, but rather reflect a general pattern of mucosal inflammatory responses to injury.