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

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 infl ammatory 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-infl ammatory 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 infl ammation. Uncovering these targets represents the primary focus of this review.