Pentoxifylline modulation of plasma membrane functions in human polymorphonuclear leukocytes.
Pentoxifylline is known to have major effects on cell membrane function in mammalian cells, including human leukocytes. The protective effects of this agent in animal models of infection and inflammation may be due to alterations in phagocyte (neutrophil and macrophage) function. However, the exact mechanism of action of pentoxifylline is unknown. In this study, we evaluated the effect of the drug on several membrane-associated activities in human polymorphonuclear neutrophils and investigated possible mechanisms for the observed changes in neutrophil function. Pentoxifylline inhibited ingestion of microbial particles (Staphylococcus aureus and zymosan); decreased superoxide generation activated by zymosan, formyl-methionyl-leucyl-phenylalanine, and concanavalin A (but not phorbol myristate acetate); and decreased uptake (transport) of adenosine stimulated by formyl-methionyl-leucyl-phenylalanine and zymosan. In contrast, pentoxifylline actually increased clindamycin uptake in zymosan-stimulated polymorphonuclear neutrophils. However, pentoxifylline had no effect on uptake of adenosine or clindamycin in unstimulated neutrophils. In comparison with known inhibitors of nucleoside transport (nitrobenzylthioinosine and dipyridamole), the results suggested that pentoxifylline does not bind to membrane nucleoside transport receptors. At concentrations which inhibit neutrophil function, pentoxifylline activity is not mediated through external membrane nucleoside regulatory sites. Thus, pentoxifylline affects the activation signal chain at a point beyond the membrane receptors. Whatever its precise mechanism of action, pentoxifylline has a striking modulatory effect on cell membrane-associated responses in stimulated leukocytes and may prove useful for control of injurious inflammatory states.
Hand
W L
WL
Veterans Administration Medical Center (Atlanta), Decatur, Georgia 30033.
Butera
M L
ML
King-Thompson
N L
NL
Hand
D L
DL
D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002981:Clindamycin / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010431:Pentoxifylline / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013805:Theobromine / Q000031:analogs & derivatives*
D013481:Superoxides; D002981:Clindamycin; D007770:L-Lactate Dehydrogenase; D000241:Adenosine; D013805:Theobromine; D010431:Pentoxifylline