Regulation of calcium homeostasis in activated human neutrophils - potential targets for anti-inflammatory therapeutic strategies
AbstractObjectives. The objectives of the current study were to: (i) present an integrated model for the restoration of calcium homeostasis in activated human neutrophils based on current knowledge and recent research; and (ii) identify potential targets for the modulation of calcium fluxes in activated neutrophils based on this model and to investigate the effects of intracellular probes which target key processes involved in calcium homeostasis and pro-inflammatory activity in these cells. Design and setting. Laboratory-based experimental research using purified human neutrophils from healthy, adult human volunteers. Outcome measures. Calcium metabolism and pro-inflammatory activity of neutrophils. Results. Modulation of calcium fluxes in activated human neutrophils can be achieved by cAMP-dependent upregulation of the activity of the endomembrane Ca2+-ATPase which resequesters cytosolic Ca2+. Formoterol, a long-acting b2-agonist, elevates intracellular cAMP levels, accelerates Ca2+ restoration in activated neutrophils and downregulates the pro-inflammatory responses of these cells. Alterations in the membrane potential of activated neutrophils may play a role in regulating calcium reuptake into the cells as attenuation of the membrane depolarisation response is associated with accelerated calcium influx. Conclusions. Modulation of the activity of the endomembrane Ca2+-ATPase in human neutrophils represents an important target for anti-inflammatory therapeutic strategies, while new insights into the role played by membrane depolarisation in regulating calcium fluxes in these cells may also facilitate development of novel anti-inflammatory agents directed against neutrophils.
(South African Medical Journal: 2002 92(12): 990-996)
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