Associate editor: A. Trifilieff
CXCR2 antagonists for the treatment of pulmonary disease

https://doi.org/10.1016/j.pharmthera.2008.10.005Get rights and content

Abstract

Chemokines have long been implicated in the initiation and amplification of inflammatory responses by virtue of their role in leukocyte chemotaxis. The expression of one of the receptors for these chemokines, CXCR2, on a variety of cell types and tissues suggests that these receptors may have a broad functional role under both constitutive conditions and in the pathophysiology of a number of acute and chronic diseases. With the development of several pharmacological, immunological and genetic tools to study CXCR2 function, an important role for this CXC chemokine receptor subtype has been identified in chronic obstructive pulmonary disease (COPD), asthma and fibrotic pulmonary disorders. Interference with CXCR2 receptor function has demonstrated different effects in the lungs including inhibition of pulmonary damage induced by neutrophils (PMNs), antigen or irritant-induced goblet cell hyperplasia and angiogenesis/collagen deposition caused by lung injury. Many of these features are common to inflammatory and fibrotic disorders of the lung. Clinical trials evaluating small molecule CXCR2 antagonists in COPD, asthma and cystic fibrosis are currently underway. These studies hold considerable promise for identifying novel and efficacious treatments of pulmonary disorders.

Introduction

Chemotactic cytokines, or chemokines, are low molecular weight proteins that were originally characterized by their ability to promote the directed chemotaxis of leukocytes. Of the different subclasses of chemokines, the CXC chemokines are notable for their role in the initiation and amplification of inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, septic shock and a number of inflammatory and fibrotic disorders of the lungs (Mukaida, 2003, Bizzarri et al., 2006). The biology of Glu-Leu-Arg (ELR+) CXC chemokines appears to extend beyond their ability to promote leukocyte chemotaxis, as the cognate receptors for these molecules, CXCR1 and CXCR2, are found on many cells other than leukocytes throughout the body. The number of publications on the functional role of CXCR2 has increased exponentially over the last 10 years due in part to the discovery of potent and selective CXCR1/CXCR2 antagonists (Podolin et al., 2002, Stevenson et al., 2005, Bizzarri et al., 2006, Chapman et al., 2007, White and Sarau, 2007, Yu et al., 2007, Walters et al., 2008), the development of neutralizing monoclonal antibodies to the receptors and their ligands (Belperio et al., 2005a, Londhe et al., 2005b, Govindaraju et al., 2006), the availability of CXCR2 knock-out mice (Del Rio et al., 2001, Johnston et al., 2005, Strieter et al., 2005a, Hallgren et al., 2007) and the identification of polymorphisms and genetic mutations of the CXCR1/CXCR2 function in human disease (Stemmler et al., 2005, Hildebrand et al., 2007).

There is a growing body of evidence indicating that CXCR2 plays an important role in pulmonary disease and several pharmaceutical companies have identified potent and selective CXCR2 antagonists that have now advanced into clinical trials. It is the purpose of this review to provide an overview of the biochemistry, biology and functional role of the CXCR2 in the lungs and to describe the potential utility of CXCR2 antagonists in pulmonary disease.

Section snippets

Biochemistry

CXCR2 was cloned in 1991 from human promyelocytic leukemia HL60 cells and identified as heptahelical G protein-coupled receptor (GPCR) for the chemokine interleukin (IL)-8/CXCL8 (Murphy & Tiffany, 1991). CXCR2 is a 360 amino acid glycoprotein that has ~78% homology at the amino acid level with CXCR1 (Holmes et al., 1991, Murphy and Tiffany, 1991). The receptor is expressed on many different cells and tissues including neutrophils, monocytes, eosinophils, mast cells, basophils, lymphocytes,

Biology

CXCR2 has been found on many different inflammatory and structural cells that regulate pulmonary functions (Fig. 2). Listed below are studies that have identified an important role for CXCR2 in the biology of each of these cell types.

Pulmonary disease

As CXCR2 is found on many of the structural and inflammatory cells in the lungs, it is not surprising to find that CXCR2 has been implicated in lung pathology in a variety of disease conditions. Listed below are studies that have identified an important role for CXCR2 in COPD, asthma, acute respiratory distress syndrome (ARDS), cystic and pulmonary fibrosis. The relative importance of CXCR2 to the pathology of each of these diseases is summarized in Table 2.

Side effect considerations

Given the suggested role of CXCR2 in mediating biological responses in several different cell types, a potential for inducing side effects and liabilities by selectively targeting of CXCR2 is evident. However, it should be noted that since many of these concerns have been identified using experimental animal models, the relevance of these observations and their translation to the clinic currently remains uncertain. As described in Section 3, a role for CXCR2 in mediating host resistance to

Conclusions

CXCR2 was first cloned in 1991 and recognized as the cognate receptor for the chemoattractant cytokine, CXCL8. Early research on the functional role for the CXCR2 implicated it as a key mediator of neutrophil chemotaxis to a variety of ELR+ CXC chemokines. With the development of a variety of pharmacological, immunological and genetic tools, a much broader role for CXCR2 has been suggested in a number of inflammatory diseases. In the lungs, CXCR2 is found on most of the inflammatory and

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