Prostaglandin, tumor necrosis factor alpha and neutrophils: causative relationship in indomethacin-induced stomach injuries.
Tumor necrosis factor alpha (TNF-alpha) has been suggested to play a critical role in indomethacin-induced gastric mucosal damage, so we evaluated its mucosal level and its relationship with prostaglandin E2 and neutrophils in indomethacin-induced gastric mucosal injury in rats. Indomethacin caused a time- and dose-dependent increase in gastric mucosal erosion, which was accompanied by a reduction in prostaglandin E2 followed by an increase in TNF-alpha level and neutrophil infiltration in the gastric mucosa. Pretreatment with exogenous prostaglandin E2 totally abolished indomethacin-induced gastric mucosal injury and the TNF-alpha increase. Depletion of neutrophils by methotrexate or reduction of TNF-alpha concentration by pentoxifylline markedly reduced indomethacin-induced mucosal damage. Pentoxifylline but not methotrexate prevented the increase in mucosal TNF-alpha level induced by indomethacin. It is suggested that depletion of prostaglandin E2 followed by an increase of TNF-alpha production and neutrophil infiltration in the gastric mucosa are important sequential processes in indomethacin-induced ulceration. Prevention of one of these processes would inhibit ulcer formation.
Ding
S Z
SZ
Department of Medicine, Faculty of Medicine, The University of Hong Kong, China.
Lam
S K
SK
Yuen
S T
ST
Wong
B C
BC
Hui
W M
WM
Ho
J
J
Guo
X
X
Cho
C H
CH
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007213:Indomethacin / Q000633:toxicity*; D007958:Leukocyte Count; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000097:blood / Q000209:etiology* / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone; D010431:Pentoxifylline; D007213:Indomethacin; D008727:Methotrexate