Classic NSAID and selective cyclooxygenase (COX)-1 and COX-2 inhibitors in healing of chronic gastric ulcers

• Published in: Microscopy research and technique 2001-06, Vol.53 (5), p.343-353
• Main Authors: Brzozowski, Tomasz, Konturek, Peter C., Konturek, Stanislaw J., Sliwowski, Zbigniew, Pajdo, Robert, Drozdowicz, Danuta, Ptak, Agata, Hahn, Eckhart G.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; aspirin; Aspirin - pharmacology; Aspirin - therapeutic use; Chronic Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - therapeutic use; Dinoprostone - biosynthesis; Dinoprostone - therapeutic use; gastric blood flow; Gastric Mucosa - blood supply; Gastric Mucosa - metabolism; Gastric Mucosa - pathology; Gastrins - blood; indomethacin; Indomethacin - pharmacology; Indomethacin - therapeutic use; interleukin 1 beta; Interleukin-1 - blood; Interleukin-1 - genetics; Interleukin-1 - metabolism; Isoenzymes - antagonists & inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Lactones - pharmacology; Lactones - therapeutic use; Male; Membrane Proteins; Nitrobenzenes - pharmacology; Nitrobenzenes - therapeutic use; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - metabolism; Radioimmunoassay; Rats; Rats, Wistar; resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Stilbenes - pharmacology; Stilbenes - therapeutic use; Stomach Ulcer - drug therapy; Stomach Ulcer - metabolism; Stomach Ulcer - pathology; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Sulfones; Thiazines - pharmacology; Thiazines - therapeutic use; Thiazoles - pharmacology; Thiazoles - therapeutic use; tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; ulcer healing; Vioxx
• ISSN: 1059-910X; 1097-0029
• DOI: 10.1002/jemt.1102

Prostaglandins (PG) derived from COX‐1 are essential for the maintenance of mucosal integrity but COX‐2 isoform synthesizes PG at a site of inflammation. Recently, COX‐2 mRNA expression was demonstrated at the ulcer edge during healing of chronic gastric ulcers but the role for expression of COX‐2 and its products such as PGE2 and cytokines including interleukin (IL‐1β) and tumor necrosis factor alpha (TNFα) in ulcer healing remains unknown. In this study, Wistar rats with gastric ulcers produced by serosal application of acetic acid (ulcer area 28 mm2) received daily treatment either with: (1) vehicle (saline); (2) NS‐398 (10 mg/kg‐d i.g.) and Vioxx (5 mg/kg‐d i.g.), both, highly specific COX‐2 inhibitors; (3) meloxicam (5 mg/kg‐d i.g.), a preferential inhibitor of COX‐2; (4) resveratrol (10 mg/kg‐d i.g.), a specific COX‐1 inhibitor; (5) indomethacin (5 mg/kg‐d i.g); and (6) aspirin (ASA; 50 mg/kg‐d i.g.), non‐selective inhibitors of both COX‐1 and COX‐2. At day 3, 7, and 14 after ulcer induction, the animals were sacrificed and the area of gastric ulcers was determined by planimetry and histology, gastric blood flow (GBF) at ulcer base and margin was measured by H2 clearance technique, and blood was withdrawn for measurement of plasma IL‐1β and TNFα levels. The mucosal biopsy samples were taken for the determination of PGE2 generation by RIA and expression of COX‐1, COX‐2, IL‐1β, and TNFα mRNA by RT‐PCR. In vehicle‐treated rats, gastric ulcers healed progressively and at day 14 the healing was completed, accompanied by a significant rise in the GBF at ulcer margin. The IL‐1β, TNFα, and COX‐1 mRNA were detected in intact and ulcerated gastric mucosa, whereas COX‐2 mRNA were upregulated only in ulcerated mucosa with peak observed at day 3 after ulcer induction. The plasma IL‐1β level was significantly increased at day 3 and 7 but then declined at day 14 to that measured in vehicle‐controls. Indomethacin and ASA, which suppressed PGE2 generation both in the non‐ulcerated and ulcerated gastric mucosa, significantly delayed the rate of ulcer healing and this was accompanied by the fall in GBF at ulcer margin and further elevation of plasma IL‐1β and TNFα levels, which was sustained up to the end of the study. Treatment with NS‐398 and Vioxx, which caused only a moderate decrease in the PGE2 generation in the non‐ulcerated gastric mucosa, delayed ulcer healing and attenuated significantly the GBF at ulcer margin and PGE2 generation in the ulcerated tissue, whi