Medicine in focus
Human neutrophil elastase: Mediator and therapeutic target in atherosclerosis

https://doi.org/10.1016/j.biocel.2008.01.004Get rights and content

Abstract

Human neutrophil elastase (HNE) is present within atherosclerotic plaques where it contributes to matrix degradation and weakening of the vessel wall associated with the complications of aneurysm formation and plaque rupture. It is joined by other extracellular proteases in these actions but the broad range of substrates and potency of HNE coupled with the potential for rapid increases in HNE activity associated with neutrophil degranulation in acute coronary syndromes single this disruptive protease out as therapeutic target in atherosclerotic disease. This review summarises the role of HNE in neutrophil-mediated endothelial injury and the evidence for HNE as a mediator of atherosclerotic plaque development. The therapeutic potential of HNE neutralising antiproteases, α-1-antitrypsin and elafin, in atherosclerosis, is discussed.

Introduction

Atherosclerosis is a chronic inflammatory disease of arterial blood vessels. Extracellular proteolysis is central to atherosclerotic plaque growth (Fig. 1) and the development of complications such as aneurysm development and plaque rupture leading to myocardial infarction (Garcia-Touchard et al., 2005). Recent work has implicated human neutrophil elastase (HNE), a serine elastase present in high concentration in neutrophil azurophilic granules, in plaque development (Dollery et al., 2003). It is a destructive protease with substrates including most components of the extracellular matrix (ECM) and its actions impact on cell and tissue function through diverse mechanisms (Lee & Downey, 2001). HNE release occurs in pathologies characterised by acute neutrophil-mediated inflammation. Neutrophil recruitment to epithelial tissues is necessary to eradicate pathogenic bacteria and HNE knockout mice have defective microbicidal activity and are predisposed to lethal gram-negative sepsis (Belaaouaj et al., 1998). The capacity of HNE to contribute to extracelluar matrix degradation and tissue injury has been demonstrated in neutrophil elastase knockout mice that do not develop as marked smoke induced emphysema compared to their wild type littermates (Shapiro et al., 2003).

Epithelial tissues are protected from excessive proteolysis by HNE and other proteases by proteinase inhibitors. These are produced locally at sites of tissue injury and by the liver which generates saturating quantities of α-1-antitrypsin, a serine proteinase inhibitor, in the circulation. Elafin and secretory leucocyte protease inhibitor are members of the four-disulphide core family with anti-HNE activity that exhibit up-regulation in response to inflammatory stimuli. They are produced by epithelial cells and form part of a reactive localised defence limiting neutrophil and HNE inflammatory injury in the lung and skin (Williams, Brown, Roghanian, & Sallenave, 2006).

The innate immune system has evolved in epithelial tissues to contain the damaging effects of neutrophils. By contrast, the capacity of vascular tissues; myocardium and arterial wall to absorb neutrophil-mediated inflammation and HNE injury is possibly less developed. These tissues are not exposed to the same environmental pressures responsible for the evolution of elaborate antiprotease defences on epithelial surfaces.

α-1-Antitrypsin is present in high concentration within the blood but its inhibitory activity may be dampened by inflammatory processes within vascular tissue such as cleavage (of α-1-antitrypsin) by matrix metalloproteases (Shapiro et al., 2003, Sires et al., 1994) and oxidative modification (Taggart et al., 2000). This would potentially leave HNE activity unchecked in diseases such as atherosclerotic plaque rupture and aneurysm formation.

This review will focus on the role of HNE in atherosclerotic disease. The contribution of HNE to neutrophil–endothelial cell interaction and injury will be discussed. Evidence for and mechanisms of HNE-mediated injury in atherosclerosis will be examined with emphasis on the physiological role and therapeutic application of antiproteases in these diseases.

Section snippets

The role of human neutrophil elastase in neutrophil-mediated endothelial injury

Endothelial function is compromised by neutrophil-mediated injury. Loss of the permeability barrier leads to oedema and haemorrhage and loss of antithrombotic activity is conducive to platelet adhesion and fibrin deposition. These effects manifest in diverse diseases that share neutrophil-mediated vascular injury as a common pathology such as adult respiratory distress syndrome, vasculitides and disseminated intravascular coagulation. Activated endothelial cells release signalling cytokines and

Antiproteases

Evidence for a deficiency of antiproteases with HNE neutralising activity being associated with more advanced atherosclerosis would support the theory that therapeutic augmentation of antiproteases would be beneficial. Recently, such an association was identified for α-1-antitrypsin in two separate lipid-lowering studies (Talmud et al., 2003). Carriers of S or Z deficiency alleles have lower levels of circulating α-1-antitrypsin and more aggressive angiographic progression of coronary disease.

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