THE ANTIINFLAMMATORY DRUG NIMESULIDE INHIBITS NEUTROPHIL ADHERENCE TOAND MIGRATION ACROSS MONOLAYERS OF CYTOKINE-ACTIVATED ENDOTHELIAL-CELLS

Neutrophil migration through the microvascular endothelium represents a fundamental event for the cell accumulation at sites of tissue injur y. Owing to their capacity to modify the structural and functional cha racteristics of endothelial cells, inflammatory cytokines such as inte rleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF alpha) play a pi votal role in directing circulating neutrophils away from the bloodstr eam to the interstitial tissue. In order to study neutrophil transendo thelial migration, human umbilical vein endothelial cells were grown t o confluence on the polycarbonate filter of two-compartment migration chambers. Pretreatment of the endothelial cell monolayers with TNF alp ha for 4 h resulted in rapid migration of approximate to 50% of subseq uently added neutrophils across the layers. In contrast, <10% of added neutrophils penetrated untreated endothelial monolayers. Using TNF al pha-treated endothelium, neutrophil transmigration was inhibited by th e methane sulfonanilide anti-inflammatory drug nimesulide. Moreover, n eutrophil adherence to TNF alpha-treated endothelial monolayers, cultu red in microtiter wells, was markedly reduced by nimesulide. A linear correlation between the drug-dependent inhibition of neutrophil transm igration and neutrophil adherence was found. Finally, nimesulide did n ot interfere with the TNF alpha ability to convert resting endothelium into a pro-adhesive and pro-locomotory cell layer. The data suggest t hat nimesulide reduces neutrophil transendothelial migration primarily by limiting the cell anchorage to the TNF alpha-activated endothelium . Therefore, the drug has the potential to down-regulate neutrophil ex travasation and, in turn, the burden of neutrophil oxidants and protea ses leading to tissue injury at sites of inflammation.