Assessment of the effect of candidate anti-inflammatory treatments on the interaction between meningococci and inflammatory cells in vitro in a whole blood model.
A wide range of immunomodulating agents are now available which may be of benefit in reducing inflammatory cell activation in meningococcal sepsis. In order to facilitate selection of candidate anti-inflammatory agents for clinical trials, we have used an in vitro whole blood model to evaluate the effects on meningococcal induced neutrophil and monocyte activation, of dexamethasone, prostacyclin, pentoxifylline and a human IgM anti-lipid A monoclonal antibody (HA-1A). Known concentrations of heat and penicillin killed meningococci were added to whole blood and the time course of cellular activation was determined. Using elastase alpha 1-antitrypsin (elastase-alpha 1-AT) and TNF alpha production as markers of neutrophil and monocyte activation respectively, plasma levels of elastase-alpha 1-AT and TNF alpha were found to increase in a dose-dependent manner. Elastase-alpha 1-AT was detected early, with most release occurring between 15-30 min whereas TNF alpha was detected later, between 120-180 min. Dexamethasone, prostacyclin and pentoxifylline caused a dose-dependent inhibition of TNF alpha release but had no effect on elastase release. HA-1A had no effect on either TNF alpha or elastase release. This model may be useful in determining the sequence of inflammatory cell activation and in selecting candidate anti-inflammatory agents for evaluation in clinical trials.
Chan
B
B
Academic Department of Paediatrics, Imperial College School of Medicine St Marys Hospital, London, UK.
Kalabalikis
P
P
Klein
N
N
Heyderman
R
R
Levin
M
M
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase / Q000032:analysis; D009000:Monocytes / Q000276:immunology*; D009345:Neisseria meningitidis / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000515:alpha 1-Antitrypsin / Q000032:analysis
D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; C037741:alpha 1-antitrypsin-leukocyte elastase complex; D019272:Leukocyte Elastase