Mechanism by which indomethacin delays the healing of acetic acid-induced ulcers in rats. Role of neutrophil antichemotactic and chemotactic activities.
We have recently discovered a neutrophil antichemotactic factor in the normal gastric mucosa of rats. In this study, we examined whether this antichemotactic factor as well as chemotactic factors are involved in the indomethacin-induced delayed healing of experimental gastric ulcers. Ulcers were induced in male rats by a submucosal injection of 20% acetic acid into the gastric wall. Experimental rats received a subcutaneous injection of indomethacin at 2 mg/kg once daily for 28 days, starting at day 0 of ulceration (defined as 5 days after acetic acid injection). In the control group (without indomethacin) antichemotactic activity was not detected in the ulcerated tissues on day 0, but gradually increased for up to 28 days. This activity did not recover in the indomethacin-treated group by day 28. However, a high level of neutrophil chemotactic activity was observed in the extract of the ulcerated area in day 0. This activity gradually declined as the ulcers healed. In the control group, chemotactic activity was negligible after dialysis of the extract. In the indomethacin-treated group, however, chemotactic activity was maintained from the 10th day after treatment, even after the extract was dialyzed. Similar to chemotactic activity, myeloperoxidase activity was also augmented significantly in the indomethacin-treated group throughout the experiment. We conclude that the mechanism by which indomethacin delays ulcer healing is associated with reduced antichemotactic activity and increased chemotactic activity in the ulcerated tissues, resulting in the persistence of neutrophil infiltration.
Fujita
H
H
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Japan.
Takahashi
S
S
Okabe
S
S
D019342:Acetic Acid; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D007213:Indomethacin / Q000494:pharmacology*; D007958:Leukocyte Count; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D014945:Wound Healing / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002630:Chemotactic Factors; D008222:Lymphokines; C034397:chemotactic inhibitory factor; D009195:Peroxidase; D015232:Dinoprostone; D019342:Acetic Acid; D007213:Indomethacin