INHIBITION OF NEUTROPHIL-DEPENDENT CYTOTOXICITY FOR HUMAN ENDOTHELIAL-CELLS BY ANTIRHEUMATIC DRUGS

Because polymorphonuclear (PMN) neutrophils are major effector cells i n vasculitides, we assessed whether disease-modifying antirheumatic dr ugs impaired the ability of human PMNs to lyse human umbilical vein en dothelial cells (HUVECs) in vitro. HUVECs were grown to confluence and labeled with chromium 51. PMNs, stimuli, and antirheumatic drugs were added stepwise, and the release of Cr-51 was subsequently assessed. L ipoxin A4 (U(A4) and the oligopeptide fMLP, activating PMNs by surface receptors, conferred highly significant cytolysis that was dose-depen dently reduced when auranofin, gold sodium aurothiomalate (GSTM), cmd sulfasalazine and its metabolites sulfapyridine and 5-ASA were added t o the assay system. This protection remained, but with stimulus- and d rug-specific variations, when either PMNs or HUVECs alone were treated with drugs before washings and PMN activation. in contrast, methotrex ate did not prefect HUVECs. Cytotoxicity conferred by the ionophore A2 3187 was inhibited by auranofin and GSTM only. Likewise, when HUVEC cy tolysis was induced by two major cytotoxic mechanisms of PMNs, exogeno us H2O2, or PMN lysates, auranofin and GSTM hampered lysis significant ly. Thus in this in vitro model of vasculitis, auranofin, GSTM, sulfas alazine, sulfapyridine, and 5-ASA-but not methotrexate-dose-dependentl y reduced the PMN-dependent endothelial cell damage by effects on the PMNs as well as effects on the HUVECs.