Abstract
In order to clarify the effects of serine protease inhibitor FUT-175 on neutrophil activation by dialysis membranes, luminol-enhanced chemiluminescence (Lu-CL) after stimulation of dialysed polymorphonuclear neutrophils (PMN) by phorbol myristate acetate (PMA) was studied in 6 chronic hemodialysis (HD) patients. In HD with heparin (2, 000u+1, 000u/hr) as an anticoagulant, Lu-CL was increased to 132±13, 165±20% of the control after 15 and 60min of HD, respectively. On the other hand, Lu-CL remained unchanged with FUT-175 (50mg+40mg/hr), indicating that FUT-175 inhibited neutrophil activation by dialysis membranes during HD. The serum FUT-175 concentration at the inlet side of the dialyzer was maintained in a range of 10-5-10-6M. Furthermore, as a parameter of superoxide anion (O2-) production, Cypridina luciferin analog (CLA)-enhanced CL (CLA-CL) was measured after stimulation of PMN from 5 healthy volunteers with either PMA or formyl-Met-Leu-Phe (fMLP). CLA-CL did not change with the addition of FUT-175 (10-4-10-7M) after the stimulation with PMA, but after the stimulation with fMLP, CLA-CL was 24.5±13, 9.9±1.0kcpm with FUT-175 at concentrations of 10-4 and 10-5M, respectively, both of which were lower than in controls, 35.0±7.5kcpm. These results suggest that FUT-175 inhibits PMN activation by dialysis membranes during HD, and that this inhibitory effect is mediated not by the inhibition of protein kinase C, but by inhibiting the activation of an fMLP-sensitive receptor on PMN by dialysis membranes.
