NSAIDS UP-REGULATE BETA(2)-INTEGRIN EXPRESSION ON HUMAN NEUTROPHILS THROUGH A CALCIUM-DEPENDENT PATHWAY

Background: Margination of circulating neutrophils (PMN) into the gast ric microcirculation is an early and critical event in the pathogenesi s of non-steroidal antinflammatory drug (NSAID)-induced gastropathy. T his effect is mediated through the upregulation of beta(2) integrins o n the PMN surface. Aims: To investigate whether indomethacin modulates : (1) Mac-1 expression; (2) Ca2+ mobilization ([Ca2+](i)), protein kin ase C and nitric oxide accumulation; and (3) mitogen-associated protei n kinase phosphorylation in human PMN. Methods: Human PMN were isolate d by centrifugation through a double Ficoll gradient. [Ca2+](i) was me asured in PMN loaded with fura-2 and Mac-1 expression by flow cytometr y. Results: Indomethacin caused a concentration- and time-dependent up regulation of CD11b and CD18 expression and PMN adhesion to endothelia l cells, Maximal upregulation of Mac-1 expression (40-50%) occurred af ter a 30-min incubation with 0.1 mM.