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TNFα processing enzyme inhibitors prevent aspirin‐induced TNFα release and protect against gastric mucosal injury in rats
Author(s) -
Stefano Fiorucci,
Elisabetta Antonelli,
Graziella Migliorati,
Luca Santucci,
Olivia Morelli,
Barbara Federici,
Antonio Morelli
Publication year - 1998
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1046/j.1365-2036.1998.00409.x
Subject(s) - tumor necrosis factor alpha , cytokine , pharmacology , aspirin , medicine , intracellular , immunology , chemistry , biochemistry
Background: Although previous studies indicate that prevention of tumour necrosis factor α (TNFα) release protects against NSAID‐induced gastric mucosal injury, intracellular pathways by which aspirin causes TNFα release are unknown. TNFα is synthesized as a precursor which is proteolytically cleaved by a specific converting enzyme, TACE, to release the mature cytokine. TACE inhibitors prevent TNFα release and protect against TNFα‐mediated disease. Aim: To investigate: (i) molecular events that regulate TNFα secretion in response to aspirin in vivo and in vitro ; (ii) whether TNFα secretion inhibitors prevent aspirin‐induced TNFα release and protect against gastric mucosal damage; and (iii) whether TNFα exerts a direct cytotoxic effect on gastric epithelial cells. Methods: In vitro studies were carried out on mouse macrophages and rat gastric mucosal cells. Gastric mucosal damage was induced in rats by oral administration of 300 mg/kg aspirin. TNFα cytotoxicity on gastric mucosal cells was examined by treating rats with lipopolysaccharide to release TNFα or by incubating dispersed gastric mucosal cells with increasing concentrations of TNFα. Results: Aspirin increases intracellular calcium (Ca 2+ ) levels and causes a time and concentration dependent increase in macrophage TNFα mRNA accumulation and cytokine release. Agents that cause Ca 2+ mobilization with a receptor‐independent mechanism, such as ionomycin and thapsigargin, stimulate TNFα release. Incubating the macrophages in a Ca 2+ free medium inhibited TNFα secretion. Agents that prevent TNFα mRNA transcription, e.g. lisophylline, PGE 2 , interleukin‐10 and 8‐BrcAMP, or TACE inhibitors, e.g. EDTA, TAPI‐2 and BB‐3103, inhibit TNFα release and protect rats against gastric mucosal injury induced by oral administration of aspirin. TNFα exerts a direct␣cytotoxic effect on gastric epithelial cells as demonstrated by the reduced viability observed in gastric mucosal␣cells prepared from rats treated with lipopolysaccharide, or␣directly incubated with increasing concentrations of TNFα. Conclusions: (i) Aspirin directly stimulates TNFα gene transcription; (ii) TACE inhibitors protect against aspirin‐induced gastric mucosal injury; and (iii) TNFα exerts a direct cytotoxic effect on gastric epithelial cells.