Inhibition of neutrophil-dependent cytotoxicity for human endothelial cells by antirheumatic drugs.
Because polymorphonuclear (PMN) neutrophils are major effector cells in vasculitides, we assessed whether disease-modifying antirheumatic drugs impaired the ability of human PMNs to lyse human umbilical vein endothelial 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 51Cr was subsequently assessed. Lipoxin A4 (LXA4) and the oligopeptide fMLP, activating PMNs by surface receptors, conferred highly significant cytolysis that was dose-dependently reduced when auranofin, gold sodium aurothiomalate (GSTM), and sulfasalazine and its metabolites sulfapyridine and 5-ASA were added to the assay system. This protection remained, but with stimulus- and drug-specific variations, when either PMNs or HUVECs alone were treated with drugs before washings and PMN activation. In contrast, methotrexate did not protect HUVECs. Cytotoxicity conferred by the ionophore A23187 was inhibited by auranofin and GSTM only. Likewise, when HUVEC cytolysis was induced by two major cytotoxic mechanisms of PMNs, exogenous H2O2, or PMN lysates, auranofin and GSTM hampered lysis significantly. Thus in this in vitro model of vasculitis, auranofin, GSTM, sulfasalazine, sulfapyridine, and 5-ASA--but not methotrexate--dose-dependently reduced the PMN-dependent endothelial cell damage by effects on the PMNs as well as effects on the HUVECs.
Bratt
J
J
Department of Rheumatology, The Karolinska Institute at Stockholm Söder Hospital, Sweden.
Palmblad
J
J
D018501:Antirheumatic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002860:Chromium Radioisotopes / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D006801:Humans; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D014471:Umbilical Veins / Q000166:cytology
D018501:Antirheumatic Agents; D002860:Chromium Radioisotopes