endothelin-1 and Oral-Ulcer

Oral ulcer is the most common oral disease and leads to pain during meals and speaking, reducing the quality of life of patients. Recent evidence using animal models suggests that oral ulcers induce cyclooxygenase-dependent spontaneous pain and cyclooxygenase-independent mechanical allodynia. Endothelin-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of endothelin-1 signaling with oral ulcer-induced pain using our proprietary assay system in conscious rats. Endothelin-1 was significantly upregulated in oral ulcers experimentally induced by topical acetic acid treatment, while endothelin-1 production was suppressed by antibacterial pretreatment. Spontaneous nociceptive behavior in oral ulcer model rats was inhibited by swab applications of BQ-788 (ET

Topics: Acetanilides; Anilides; Animals; Bridged Bicyclo Compounds; Caproates; Cinnamates; Disease Models, Animal; Endothelin-1; Male; Oligopeptides; Oral Ulcer; Pain; Peptides, Cyclic; Piperidines; Purines; Rats; Rats, Wistar; Signal Transduction; Sulfonamides; TRPV Cation Channels

Leptin, a multifunctional hormone that regulates food intake and energy expenditure, has emerged recently as an important modulator of inflammatory cascades associated with wound healing. In this study, we applied the animal model of buccal mucosal ulcer to investigate the role of endothelin-1 (ET-1) and leptin in soft oral tissue repair. Using groups of rats with experimentally induced buccal mucosal ulcers we show that ulcer onset was characterized by a marked increase in the mucosal level of ET-1 and leptin. However, while the ET-1 level gradually declined with healing, the mucosal level of leptin increased reaching maximum expression on the 4th day of healing. Therapeutic administration of phosphoramidon, an inhibitor of ECE-1 activity, not only led to a 53.2% drop in the ET-1, but also produced a dose-dependent reduction (up to 50.9%) in the mucosal level of leptin and up to 42.3% decline in the rate of ulcer healing. A marked drop (54.2%) in the mucosal level of leptin and the reduction (46.8%) in the rate of ulcer healing was also attained in the presence of ETA receptor antagonist BQ610 administration, but not the ETB receptor antagonist BQ788. Moreover, administration of ERK inhibitor, PD98059 in the presence of ETB receptor antagonist, but not the ETA receptor antagonist, caused the reduction the mucosal leptin level as well as a decline in the rate of ulcer healing. Our findings are the first to implicate the requirement for both ET-1 and leptin in orderly progression of the events of soft oral tissue repair. We also show that ET-1 is a key factor in up-regulation of leptin production associated with oral mucosal ulcer healing , and that the effect of ET-1 on leptin production is a consequence of ETA receptor activation and subsequent signaling through MAPK/ERK.

Topics: Acetic Acid; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Flavonoids; Glycopeptides; Leptin; Metalloendopeptidases; Mitogen-Activated Protein Kinase Kinases; Mouth Mucosa; Oligopeptides; Oral Ulcer; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Up-Regulation; Wound Healing