Review
Interleukin-8 receptor antagonists in pulmonary diseases

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Abstract

Inflammatory cells are thought to be instrumental in the pathophysiology of pulmonary diseases, and control of their recruitment and activation in the lung would appear to be an attractive strategy for therapeutic intervention. Interleukin-8 and related CXC chemokines are involved in the function of neutrophils and T cells, and have been implicated in several lung diseases. Small-molecule antagonists of the interleukin-8 receptors have been identified, which may help elucidate the role of interleukin-8 and related chemokines in the pathophysiology of lung diseases.

Introduction

Interleukin-8 (IL-8) was the first member identified of a growing family (currently more than 40 members) of pro-inflammatory chemokines that attract and activate immune and inflammatory cells. A diverse variety of biological effects are attributed to IL-8, including several involving neutrophils: inflammatory cell activation and chemotaxis, production of reactive oxygen species, increased expression of the integrin CD11b–CD18, enhancement of cell adhesion to endothelial cells, promotion of angiogenesis, modulation of histamine release and the release of azurophil granules [1]. IL-8 activates a number of inflammatory cells in addition to human neutrophils, for example T cells, B cells, basophils, IL-2-activated natural killer cells and granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3-stimulated eosinophils 2., 3.. The predominant form of IL-8 is a nonglycosylated 72-amino-acid protein that is produced by many cells, including neutrophils, monocytes, macrophages, mast cells, vascular endothelial cells, stromal cells and epithelial cells. 1., 4.. The biological effects of IL-8 and related chemokines are mediated through two seven-transmembrane-domain G-protein-coupled receptors, designated CXCR1 and CXCR2 (CXC chemokine receptor 1 and 2) 2., 5..

Section snippets

Interleukin-8 receptors

The CXC chemokine receptors (α-chemokine family of receptors), presently have six members that are activated by CXC chemokines; some of these chemokines contain the Glu-Leu-Arg (ELR) sequence before the first cysteine residue. Those containing the ELR sequence act at both CXCR1 and CXCR2, which share 85% amino acid identity 6., 7.. CXCR1 is selectively activated by IL-8 and granulocyte chemotactic protein 2 (GCP-2), whereas CXCR2 is stimulated potently by IL-8, epithelial-derived

Potential role of interleukin-8 in lung disease

Recruitment of inflammatory cells in response to tissue injury is a normal physiological response to fight infection, remove damaged or dead cells and stimulate healing; however, excessive recruitment of these cells results in tissue damage and slows the rate of healing. In a number of pulmonary disorders, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis and bacterial pneumonia, IL-8 appears to be important for the

Interleukin-8 receptor antagonists

Most animal studies have utilised antibodies to antagonise the activity of specific chemokines. This is useful when a single chemokine is responsible for the activity observed, but in most cases multiple chemokines activate a receptor (e.g. CXCR2), and other types of antagonist approaches are required (e.g. receptor antagonists or receptor mAbs).

Its been shown that amino-terminal truncation of IL-8 and amino-acid modification of the ELR+ motif of related chemokines can produce antagonists of

Conclusions

There is considerable evidence to suggest that the recruitment and activation of inflammatory cells in the lung contributes significantly to the pathophysiology of pulmonary diseases. IL-8 and related chemokines are found at elevated concentrations in the circulation and in the lungs of patients with different pulmonary diseases, including COPD, ARDS and asthma. The biological activity of these chemokines is mediated by two populations of cell-surface receptors, CXCR1 and CXCR2, on neutrophils,

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • •. of special interest

  • •• of outstanding interest

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