S. Fiorucci et al., TNF alpha processing enzyme inhibitors prevent aspirin-induced TNF alpha release and protect against gastric mucosal injury in rats., ALIM PHARM, 12(11), 1998, pp. 1139-1153
Background: Although previous studies indicate that prevention of tumour ne
crosis factor alpha (TNF alpha) release protects against NSAID-induced gast
ric mucosal injury, intracellular pathways by which aspirin causes TNF alph
a release are unknown, TNF alpha is synthesized as a precursor which is pro
teolytically cleaved by a specific converting enzyme, TACE, to release the
mature cytokine. TACE inhibitors prevent TNF alpha release and protect agai
nst TNF alpha-mediated disease,
Aim: To investigate: (i) molecular events that regulate TNF alpha secretion
in response to aspirin in vivo and in vitro; (ii) whether TNF alpha secret
ion inhibitors prevent aspirin-induced TNF alpha release and protect agains
t gastric mucosal damage; and (iii) whether TNF alpha exerts a direct cytot
oxic effect on gastric epithelial cells.
Methods: In vitro studies were carried out on mouse macrophages and rat gas
tric mucosal cells, Gastric mucosal damage was induced in rats by oral admi
nistration of 300 mg/kg aspirin. TNF alpha cytotoxicity on gastric mucosal
cells was examined by treating rats with lipopolysaccharide to release TNF
alpha or by incubating dispersed gastric mucosal cells with increasing conc
entrations of TNF alpha.
Results: Aspirin increases intracellular calcium (Ca2+) levels and causes a
time and concentration dependent increase in macrophage TNF alpha mRNA acc
umulation and cytokine release. Agents that cause Ca2+ mobilization with a
receptor-independent mechanism, such as ionomycin and thapsigargin, stimula
te TNFa release. Incubating the macrophages in a Ca2+ free medium inhibited
TNF alpha secretion, Agents that prevent TNF alpha mRNA transcription, e.g
, lisophylline, PGE(2), interleukin-10 and 8-BrcAMP, or TACE inhibitors, e.
g. EDTA, TAPI-2 and BB-3103, inhibit TNF alpha release and protect rats aga
inst gastric mucosal injury induced by oral administration of aspirin, TNF
alpha exerts a direct cytotoxic effect on gastric epithelial cells as demon
strated by the reduced viability observed in gastric mucosal cells prepared
from rats treated with lipopolysaccharide, or directly incubated with incr
easing concentrations of TNF alpha,
Conclusions: (i) Aspirin directly stimulates TNF alpha gene transcription;
(ii) TACE inhibitors protect against aspirin-induced gastric mucosal injury
; and (iii) TNF alpha exerts a direct cytotoxic effect on gastric epithelia
l cells.