Taming the neutrophil: calcium clearance and influx mechanisms as novel targets for pharmacological control

Abstract

Summary Neutrophils are relatively insensitive to the anti-inflammatory actions of conventional chemotherapeutic agents, including corticosteroids, emphasizing the requirement for novel pharmacological strategies to control the potentially harmful proinflammatory activities of these cells. In the case of commonly-occurring inflammatory diseases of the airways, the neutrophil is the primary mediator of inflammation in conditions such as chronic obstructive pulmonary disease, cystic fibrosis, acute respiratory distress syndrome, bronchiectasis and non-eosinophilic bronchial asthma. Recent insights into the mechanisms utilized by neutrophils to restore Ca2+ homeostasis following activation with Ca2+-mobilizing, proinflammatory stimuli have facilitated the identification of novel targets for anti-inflammatory chemotherapy in these cells. The most amenable of these from a chemotherapeutic perspective, is the cyclic AMP-dependent protein kinase-modulated endomembrane Ca2+-ATPase which promotes clearance of the cation from the cytosol of activated neutrophils. Second generation type 4 phosphodiesterase inhibitors and adenosine receptor agonists operative at the level of subtype A2A adenosine receptors, which are currently undergoing clinical and preclinical assessment respectively, hold promise as pharmacologic modulators during the restoration of Ca2+ homeostasis. If this promise is realized, it may result in novel chemotherapeutic strategies for the control of hyperacute and chronic inflammatory conditions in which neutrophils are primary offenders. Alternative, potential future targets include the Na+, Ca2+-exchanger and store-operated Ca2+ channels, which cooperate in the refilling of intracellular Ca2+ stores.