Effect of ingested pentoxifylline on neutrophil superoxide anion production.
Superoxide and other oxygen radicals produced by activated polymorphonuclear leukocytes (PMN) may be important causes of tissue damage in a number of inflammatory conditions. Therefore, a drug which suppresses PMN responses in vivo is potentially important. In vitro, pentoxifylline (PTOX) inhibits superoxide anion production when PMN are stimulated with an activated complement component (C5a Des Arg) or formyl peptides but only at concentrations not achieved in the circulation. The aim of this study was to determine whether PTOX has an effect on PMN responses in vivo. Superoxide anion production, monitored by lucigenin-enhanced chemiluminescence, was inhibited by 40.5% +/- 8.0% (n = 8, P < 0.009) for C5a Des Arg and 47.7% +/- 9.6% (n = 8, P < 0.009) for formyl-methionylleucylphenylalanine stimulation 1.5 h after ingestion of 400 mg of PTOX in a slow-release tablet, with some inhibitory effects persisting at 5 h. There was a strong correlation between reduced PMN response to activated complement and plasma concentrations of three PTOX metabolites (P < 0.05), but not with plasma concentrations of the parent drug. In vitro investigations with each of the four methylxanthines showed two of these metabolites to be most effective at reducing PMN respiratory burst activity, lactoferrin release, and the expression of CD11b and CD18 molecules. Furthermore, this in vitro inhibitory activity was achieved at concentrations of metabolites achievable in vivo. The results suggest that PTOX reduces oxygen radical production and protects against unwanted tissue damage in vivo by the action of its metabolites.
Medical Research Centre, City Hospital, Nottingham, United Kingdom.
S P
SP
Crouch
J
J
Fletcher
D000284:Administration, Oral; D015703:Antigens, CD / Q000378:metabolism; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010431:Pentoxifylline / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D016897:Respiratory Burst / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism*; D014970:Xanthines / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology
D015703:Antigens, CD; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D016177:Macrophage-1 Antigen; D014970:Xanthines; D013481:Superoxides; C008514:methylxanthine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015054:Zymosan; D007781:Lactoferrin; D010431:Pentoxifylline