Pharmacological control of neutrophil-mediated inflammation: Strategies targeting calcium handling by activated polymorphonuclear leukocytes

Gregory R Tintinger, Helen C Steel, Annette J Theron, Ronald Anderson

Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, University of Pretoria and Tshwane Academic Division of the National Health Laboratory Service, Pretoria, South Africa

Abstract: Unlike most other effector cells of the innate, as well as the adaptive immune systems, the neutrophil is a relatively undiscerning aggressor with scant regard for damage limitation. Although this highly combative, professional phagocyte has become increasingly implicated in the immunopathogenesis of many acute and chronic inflammatory disorders, of both infective and noninfective origin, effective pharmacological strategies to counter neutrophil aggression have remained elusive. Activation of neutrophils results in rapid mobilization of both stored and extracellular Ca²⁺, resulting in abrupt, usually transient increases in cytosolic Ca²⁺, which precede, and are a prerequisite for activation of the Ca²⁺-dependent pro-inflammatory activities of these cells. Mobilization of Ca²⁺ by, and restoration of Ca²⁺ homeostasis to activated neutrophils are multistep processes which present a number of potential targets, some well recognized and others novel and unconventional, for the pharmacological control of neutrophil-mediated inflammation. Uncovering these targets represents the primary focus of this review.

Keywords: calcium, cyclic AMP, NADPH oxidase, neutrophils, sodium-calcium exchanger