Mediators of complement-independent granulocyte activation during haemodialysis: role of calcium, prostaglandins and leukotrienes.
Granulocyte activation during haemodialysis using cuprophane membrane is mediated by complement-derived anaphylatoxins C3a and C5a. However, neutrophil degranulation induced by modified cellulosic membranes or synthetic membranes does not correlate with C3a or C5a concentrations. Incubation and recirculation experiments were performed to find out which messengers trigger neutrophil degranulation during blood contact with different membrane materials. During in vitro haemodialysis for 2 hours, PMMA and cuprophane induced pronounced degranulation of neutrophils. With PMMA this was associated with increased thromboxane B2 but low C3a levels, while with cuprophane membrane, marked complement activation but only little thromboxane B2 release was observed. Indomethacin (10 microM) nullified all thromboxane B2 response but could not influence elastase release, indicating that cyclo-oxygenase products are not involved in neutrophil degranulation under these conditions. During incubation of blood with dialysis membranes, inhibition of lipoxygenase by esculetin or of phospholipase A2 by hydrocortisone also had no effect on neutrophil degranulation. One messenger involved in granulocyte activation might be free cytosolic calcium. Application of different calcium channel blockers (verapamil, diltiazem, or nitrendipine) did not influence neutrophil degranulation in incubation experiments, in PMMA or cuprophane membranes. In contrast, chelation of plasmatic calcium by sodium citrate or EDTA blunted elastase release induced by these membranes. This study indicates that calcium is a key mediator required for neutrophil degranulation in complement-activating and non-complement-activating dialysis membranes, while activation of the prostaglandin or leukotriene cascade are not required.
Böhler
J
J
Department of Nephrology, University of Freiburg, Germany.
Donauer
J
J
Birmelin
M
M
Schollmeyer
P J
PJ
Hörl
W H
WH
D000328:Adult; D001775:Blood Circulation; D002118:Calcium / Q000502:physiology*; D015550:Cell Degranulation / Q000187:drug effects; D002482:Cellulose / Q000031:analogs & derivatives / Q000494:pharmacology; D002951:Citrates / Q000494:pharmacology; D019343:Citric Acid; D003165:Complement System Proteins / Q000502:physiology; D006098:Granulocytes / Q000502:physiology*; D006801:Humans; D015289:Leukotrienes / Q000502:physiology*; D008567:Membranes, Artificial; D008768:Methylmethacrylates / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D010196:Pancreatic Elastase / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology*; D006435:Renal Dialysis
D002951:Citrates; D015289:Leukotrienes; D008567:Membranes, Artificial; D008768:Methylmethacrylates; D011453:Prostaglandins; D019343:Citric Acid; D002482:Cellulose; D003165:Complement System Proteins; C009865:cuprammonium cellulose; D010196:Pancreatic Elastase; D002118:Calcium