Inhibition of the inflammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline.
Inflammatory cytokines, including interleukin-1 and tumor necrosis factor, are produced by monocytes and macrophages in response to microorganisms and microbial products such as endotoxins. The cytokines stimulate neutrophil adherence, degranulation, and superoxide production but inhibit neutrophil migration. We studied the modulation of cytokine-induced neutrophil activation by pentoxifylline and its principle metabolites. Lipopolysaccharide-stimulated mononuclear-leukocyte-conditioned medium containing inflammatory cytokines, purified human interleukin-1, or recombinant human tumor necrosis factor increased neutrophil adherence to nylon fiber, primed neutrophils for increased superoxide production in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), increased neutrophil lysozyme release stimulated by FMLP, and decreased directed migration of neutrophils to FMLP. Pentoxifylline and its principle metabolites at or near therapeutically achievable levels were able to counteract these effects. Pentoxifylline inhibited the increase in free intracellular calcium in polymorphonuclear leukocytes stimulated by FMLP and increased binding of FMLP to neutrophils at 37 degrees C but not at 4 degrees C. By blocking the inflammatory action of interleukin-1 and tumor necrosis factor on neutrophils, pentoxifylline may diminish the tissue damage caused by neutrophils in such conditions as septic shock, adult respiratory distress syndrome, cardiopulmonary bypass lung damage, and myocardial reperfusion injury.
Sullivan
G W
GW
Department of Internal Medicine, University of Virginia Medical Center, Charlottesville 22908.
Carper
H T
HT
Novick
W J
WJ
Mandell
G L
GL
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002118:Calcium; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000201:enzymology; D003600:Cytosol / Q000378:metabolism; D005609:Free Radicals; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010431:Pentoxifylline / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000187:drug effects; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013481:Superoxides / Q000096:biosynthesis; D013805:Theobromine / Q000031:analogs & derivatives*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D003470:Culture Media; D005609:Free Radicals; D007375:Interleukin-1; D008070:Lipopolysaccharides; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013805:Theobromine; D010431:Pentoxifylline; D002118:Calcium