A model of the oscillatory metabolism of activated neutrophils.
We present a two-compartment model to explain the oscillatory behavior observed experimentally in activated neutrophils. Our model is based mainly on the peroxidase-oxidase reaction catalyzed by myeloperoxidase with melatonin as a cofactor and NADPH oxidase, a major protein in the phagosome membrane of the leukocyte. The model predicts that after activation of a neutrophil, an increase in the activity of the hexose monophosphate shunt and the delivery of myeloperoxidase into the phagosome results in oscillations in oxygen and NAD(P)H concentration. The period of oscillation changes from >200 s to 10-30 s. The model is consistent with previously reported oscillations in cell metabolism and oxidant production. Key features and predictions of the model were confirmed experimentally. The requirement of the hexose monophosphate pathway for 10 s oscillations was verified using 6-aminonicotinamide and dexamethasone, which are inhibitors of glucose-6-phosphate dehydrogenase. The role of the NADPH oxidase in promoting oscillations was confirmed by dose-response studies of the effect of diphenylene iodonium, an inhibitor of the NADPH oxidase. Moreover, the model predicted an increase in the amplitude of NADPH oscillations in the presence of melatonin, which was confirmed experimentally. Successful computer modeling of complex chemical dynamics within cells and their chemical perturbation will enhance our ability to identify new antiinflammatory compounds.
Olsen
Lars F
LF
European Media Laboratory, Schloss-Wolfsbrunnenweg 33, D-69118 Heidelberg, Germany. lfo@dou.dk
Kummer
Ursula
U
Kindzelskii
Andrei L
AL
Petty
Howard R
HR
D002384:Catalysis; D002478:Cells, Cultured; D003067:Coenzymes / Q000378:metabolism; D003198:Computer Simulation; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D009097:Multienzyme Complexes / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D018375:Neutrophil Activation / Q000502:physiology*; D009504:Neutrophils / Q000737:chemistry / Q000378:metabolism*; D009991:Oscillometry; D010100:Oxygen / Q000378:metabolism; D010507:Periodicity; D009195:Peroxidase / Q000378:metabolism*; D010544:Peroxidases / Q000378:metabolism; D012680:Sensitivity and Specificity
D003067:Coenzymes; D008081:Liposomes; D009097:Multienzyme Complexes; D006735:Horseradish Peroxidase; D010544:Peroxidases; D009195:Peroxidase; D019255:NADPH Oxidases; D008550:Melatonin; D010100:Oxygen