ISSN:
1365-2036
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Margination of circulating neutrophils (PMN) into the gastric microcirculation is an early and critical event in the pathogenesis of non-steroidal antinflammatory drug (NSAID)-induced gastropathy. This effect is mediated through the upregulation of β2 integrins on the PMN surface.〈section xml:id="abs1-2"〉〈title type="main"〉Aims:To investigate whether indomethacin modulates: (1) Mac-1 expression; (2) Ca2+ mobilization ([Ca2+]i), protein kinase C and nitric oxide accumulation; and (3) mitogen-associated protein kinase phosphorylation in human PMN.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Human PMN were isolated by centrifugation through a double Ficoll gradient. [Ca2+]i was measured in PMN loaded with fura-2 and Mac-1 expression by flow cytometry.〈section xml:id="abs1-4"〉〈title type="main"〉Results:Indomethacin caused a concentration- and time-dependent upregulation of CD11b and CD18 expression and PMN adhesion to endothelial cells. Maximal upregulation of Mac-1 expression (40–50%) occurred after a 30-min incubation with 0.1 mM indomethacin. The effect was prevented by removing the Ca2+. Ionomycin and thapsigargin caused a 7–10-fold increase in [Ca2+]i and a 2–4-fold increase in Mac-1 expression. Indomethacin induced a concentration-dependent phosphorylation of a 41-kDa mitogen-associated protein kinase. Tyrosine kinase inhibitors prevented the effect of indomethacin on Mac-1 expression and Ca2+ mobilization. Indomethacin and ionomycin increased superoxide generation, myeloperoxidase secretion and PMN adherence to endothelial cells and stimulated nitric oxide production. Indomethacin-induced Mac-1 upregulation was prevented by a nitric oxide synthase inhibitor.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:Indomethacin-induced upregulation of Mac-1 is mediated by changes in [Ca2+]i and nitric oxide. Phosphorylation of the 41-kDa mitogen-associated protein isoform is a previously unreported target of NSAID action. These effects might help to explain the ability of indomethacin to cause gastric neutrophil margination.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1365-2036.1997.00190.x
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