Associate editor: A. TrifilieffCXCR2 antagonists for the treatment of pulmonary disease
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
References (200)
- et al.
Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2
Blood
(2005) - et al.
The CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor
J Biol Chem
(1996) Asthma and chronic obstructive pulmonary disease
- et al.
ELR+ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets
Pharmacol Ther
(2006) - et al.
Up-regulated expression of the CXCR2 ligand KC/GRO-{alpha} in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression
Am J Pathol
(2006) - et al.
The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner
Blood
(2005) - et al.
C(4)-alkyl substituted furanyl cyclobutenediones as potent, orally bioavailable CXCR2 and CXCR1 receptor antagonists
Bioorg Med Chem Lett
(2007) - et al.
Cystic fibrosis: the mechanisms of pathogenesis of an inherited lung disorder
Drug Discov Today: Disease Mechanisms
(2007) - et al.
Expression of multiple functional chemokine receptors and monocyte chemoattractant protein-1 in human neurons
Neuroscience
(2000) - et al.
Socs3 maintains the specificity of biological responses to cytokine signals during granulocyte and macrophage differentiation
Exp Hematol
(2008)