Targeting of a common receptor shared by CXCL8 and N-Ac-PGP as a therapeutic strategy to alleviate chronic neutrophilic lung diseases

doi:10.1016/j.ejphar.2011.05.073

European Journal of Pharmacology

Volume 667, Issues 1–3, 30 September 2011, Pages 1-5

https://doi.org/10.1016/j.ejphar.2011.05.073 Get rights and content

Abstract

Persistent neutrophilia is implicated in the pathology of several chronic lung diseases and consequently targeting the signals that drive the recruitment of these cells offers a plausible therapeutic strategy. The tripeptide Pro–Gly–Pro (PGP) is a neutrophil chemoattractant derived from extracellular matrix collagen and implicated in diseases such as COPD and cystic fibrosis. It was anticipated that PGP exerts its chemoatactic activity by mimicking key sequences found within classical neutrophil chemokines, such as CXCL8, and binding their receptors, CXCR1/2. Recently, however, the role of CXCR1/2 as the receptors for PGP has been questioned. Three studies published in the European Journal of Pharmacology (Vol.668/Issue 3) address this controversy and demonstrate CXCR1/2 to be a common receptor for CXCL8 and PGP. Accordingly, these studies demonstrate the therapeutic potential of targeting this shared receptor to simultaneously alleviate neutrophilic inflammation driven by multiple neutrophil chemoattractants.

Research Highlights

► Persistent neutrophilia is implicated in the pathology of chronic lung diseases. ► Collagen-derived tripeptide, Pro-Gly-Pro (PGP), is a neutrophil chemoattractant. ► PGP is observed in chronic lung diseases such as COPD. ► PGP signals through CXCR1/2, the same receptors used by neutrophil chemokine CXCL8. ► Targeting shared receptors CXCR1/2 may alleviate neutrophilic inflammation.

Section snippets

Acknowledgements

RJS is supported by The Wellcome Trust (082727/Z/07/Z).

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Excessive inflammation caused by the recruited neutrophils is thought, at least partially, to be responsible for COPD, asthma, inflammatory bowel diseases, and Crohn's disease. Hence, targeting CXCR1 using structural and biochemical approaches to develop specific antagonists is a promising therapeutic strategy to modulate the receptor activity to combat these diseases (Bizzarri et al., 2006; Panina, Mariani, & D'Ambrosio, 2006; Snelgrove, 2011). Additionally, CXCR1 promotes IL-8-mediated tumor growth such as prostate cancer (Shamaladevi, Lyn, Escudero, & Lokeshwar, 2009), breast cancer (Ginestier et al., 2010), colorectal cancer, and melanoma (Sharma, Singh, Varney, & Singh, 2010), and the CXCR1 blockade provides a possible therapeutic intervention point in targeting the tumor microenvironment.
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PerspectiveTargeting of a common receptor shared by CXCL8 and N-Ac-PGP as a therapeutic strategy to alleviate chronic neutrophilic lung diseases

Abstract

Research Highlights

Section snippets

Acknowledgements

Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease

Am. J. Respir. Crit. Care Med.

Hit-to-lead studies: the discovery of potent, orally bioavailable thiazolopyrimidine CXCR2 receptor antagonists

Bioorg. Med. Chem. Lett.

Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4

Chest

Store-operated channels: diversity and activation mechanisms

Sci. STKE

Cigarette smoke-induced lung emphysema in mice is associated with prolyl endopeptidase, an enzyme involved in collagen breakdown

Am. J. Physiol. Lung Cell. Mol. Physiol.

CXCR2 antagonists block the N-Ac-PGP-induced neutrophil influx in the airways of mice, but not the production of the chemokine CXCL1

Eur. J. Pharmacol.

CXCR2 antagonists for the treatment of pulmonary disease

Pharmacol. Ther.

Structural requirements for interleukin-8 function identified by design of analogs and CXC chemokine hybrids

J. Biol. Chem.

Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4

Eur. Respir. J.

The collagen-breakdown product N-acetyl-Proline-Glycine-Proline (N-alpha-PGP) does not interact directly with human CXCR1 and CXCR2

Eur. J. Pharmacol.

Attacking the multi-tiered proteolytic pathology of COPD: new insights from basic and translational studies

Pharmacol. Ther.

A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation

J. Immunol.

Bioactivity of peptide analogs of the neutrophil chemoattractant, N-acetyl-proline-glycine-proline

Invest. Ophthalmol. Vis. Sci.

The presence of a matrix-derived neutrophil chemoattractant in bronchiolitis obliterans syndrome after lung transplantation

J. Immunol.

SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects

Eur Respir J

A CXCL8 receptor antagonist based on the structure of N-acetyl-proline-glycine-proline

Eur. J. Pharmacol.

Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma

Am. J. Respir. Crit. Care Med.

Activation of CXCR2 by extracellular matrix degradation product acetylated-pro-gly-pro has therapeutic effects against sepsis

Am. J. Respir. Crit. Care Med.

Chemokines — chemotactic cytokines that mediate inflammation

N. Engl. J. Med.

The molecular biology of leukocyte chemoattractant receptors

Annu. Rev. Immunol.

Inflammatory cells in the airways in COPD

Thorax

N-alpha-PGP and PGP, potential biomarkers and therapeutic targets for COPD

Respir. Res.

Perspective
Targeting of a common receptor shared by CXCL8 and N-Ac-PGP as a therapeutic strategy to alleviate chronic neutrophilic lung diseases