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Effect of ingested pentoxifylline on neutrophil superoxide anion production
1Medical Research Centre, City Hospital, Nottingham, United Kingdom.
Abstract:
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.
Insights
Pentoxifylline (PTOX) metabolites, not the parent drug, effectively suppress damaging oxygen radical production by polymorphonuclear leukocytes (PMN) in vivo. This suggests PTOX
Area of Science:
- Immunology
- Pharmacology
- Biochemistry
Background:
- Activated polymorphonuclear leukocytes (PMN) produce superoxide and oxygen radicals, contributing to tissue damage in inflammatory conditions.
- Pentoxifylline (PTOX) inhibits PMN superoxide production in vitro, but at concentrations not typically achieved in circulation.
Purpose of the Study:
- To investigate the in vivo effects of pentoxifylline (PTOX) on polymorphonuclear leukocyte (PMN) responses.
- To determine if PTOX or its metabolites are responsible for inhibiting PMN activity in vivo.
Main Methods:
- In vivo assessment of superoxide anion production in PMN using lucigenin-enhanced chemiluminescence after PTOX administration.
- Correlation analysis between PMN response, plasma concentrations of PTOX and its metabolites.
- In vitro evaluation of methylxanthine metabolites on PMN respiratory burst and molecule expression.
Main Results:
- PTOX administration significantly inhibited PMN superoxide anion production in vivo.
- Inhibition of PMN response correlated with plasma concentrations of PTOX metabolites, not the parent drug.
- Specific PTOX metabolites demonstrated potent in vitro inhibition of PMN activity at achievable concentrations.
Conclusions:
- Pentoxifylline (PTOX) reduces in vivo oxygen radical production and protects against inflammatory tissue damage primarily through its active metabolites.
- The therapeutic effects of PTOX in inflammatory conditions are likely mediated by its metabolites acting on PMN function.