Abstract
Activation of neutrophils is a critically important component of the innate immune response to bacterial and chemical stimuli, and culminates in the “neutrophil burst”, which facilitates neutrophil phagocytosis via the release of superoxide anion radical (O2−) from NADPH oxidase. Excessive and/or prolonged neutrophil activation results in substantial tissue injury and increases in vascular permeability—resulting in sustained tissue infiltration with neutrophils and monocytes, and persistent vasomotor dysfunction. Cardiovascular examples of such changes include acute and chronic systolic and diastolic heart failure (“heart failure with preserved ejection fraction”), and the catecholamine-induced inflammatory disorder takotsubo syndrome. We have recently demonstrated that B-type natriuretic peptide (BNP), acting via inhibition of activation of neutrophil NADPH oxidase, is an important negative modulator of the “neutrophil burst”, though its effectiveness in limiting tissue injury is partially lost in acute heart failure. The potential therapeutic implications of these findings, regarding the development of new means of treating both acute and chronic cardiac injury states, are discussed.
Highlights
The latter is engendered by a transient process usually termed the “neutrophil burst,” whereby activation of the neutrophil isoform of NADPH oxidase results in the production of large quantities of the superoxide (O2−) anion radical, together with secondary increases in the generation of hydrogen peroxide and hypochlorous acid (HOCl) [1]
B-type natriuretic peptide (BNP) acts through binding to natriuretic peptide receptor A (NPR-A, equivalent to particulate guanylate cyclase-A [pGC-A]) which results in the generation of the second messenger cGMP [29]
We initially studied normal subjects to determine the effects of exogenous BNP on the “neutrophil burst” and associated myeloperoxidase (MPO) release
Summary
Neutrophils, as a pivotal component of the innate immune system, make fundamental contributions to host defense against invading micro-organisms. The most important aspect of this role is the phagocytic function of neutrophils, consisting of the engulfing of bacteria into lysosomes, within which they are exposed to potentially lethal oxidative stress The latter is engendered by a transient process usually termed the “neutrophil burst,” whereby activation of the neutrophil isoform of NADPH oxidase results in the production of large quantities of the superoxide (O2−) anion radical, together with secondary increases in the generation of hydrogen peroxide and hypochlorous acid (HOCl) [1]. Termination of the inflammatory process initiated in association with neutrophil activation potentially begins at the time of neutrophil apoptosis, leading to what is normally a brief but potent phagocytic response. The remainder of this review will focus on potential ways of limiting inappropriately severe and/or prolonged neutrophil-initiated tissue inflammation, with particular reference to the role of BNP, before proceeding to briefly discuss some forms of disease affecting the myocardium where this pathophysiological interaction may represent a therapeutic opportunity
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