A novel peptide cxcr ligand derived from extracellular matrix degradation during airway inflammation

ABSTRACT We describe the tripeptide neutrophil chemoattractant N-acetyl Pro-Gly-Pro (PGP), derived from the breakdown of extracellular matrix (ECM), which shares sequence and structural

homology with an important domain on alpha chemokines. PGP caused chemotaxis and production of superoxide through CXC receptors, and administration of peptide caused recruitment of

neutrophils (PMNs) into lungs of control, but not CXCR2-deficient mice. PGP was generated in mouse lung after exposure to lipopolysaccharide, and _in vivo_ and _in vitro_ blockade of PGP

with monoclonal antibody suppressed PMN responses as much as chemokine-specific monoclonal antibody. Extended PGP treatment caused alveolar enlargement and right ventricular hypertrophy in

mice. PGP was detectable in substantial concentrations in a majority of bronchoalveolar lavage samples from individuals with chronic obstructive pulmonary disease, but not control

individuals. Thus, PGP's activity links degradation of ECM with neutrophil recruitment in airway inflammation, and PGP may be a biomarker and therapeutic target for neutrophilic

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Scholar  Download references ACKNOWLEDGEMENTS The authors acknowledge J. Downs (Pfizer Inc.) for the gift of the 9A4 monoclonal antibody, the laboratory of J. Oppenheim (US National

Institutes of Health) for providing the CXCR-transfected cells, and P. O'Reilley, W. Bailey and K. Young for advice. We thank S. Parker of the University of Alabama at Birmingham (UAB)

Core Facility for Collection, Processing and Storage of Alveolar Fluid for clinical samples and the UAB Mass Spectrometry Core Facility for sample analysis. This work was supported by US

National Institutes of Health grants HL68806 (to J.E.B.), T32HL007553 (to B.D.N.), T32 GM63490 (to B.D.N.), T32 GM008361 (to N.M.W.) and F30 ES13874 (to N.M.W.). AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * Department of Physiology and Biophysics, University of Alabama at Birmingham, 1918 University Boulevard, Birmingham, 35294, Alabama, USA Nathaniel M Weathington, Brett D

Noerager, Patricia L Jackson, F Shawn Galin & J Edwin Blalock * Department of Phamacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University,

Sorbonnelaan 16, Utrecht, 3584 CA, The Netherlands Anneke H van Houwelingen, Aletta D Kraneveld, Gert Folkerts & Frans P Nijkamp Authors * Nathaniel M Weathington View author

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Correspondence to J Edwin Blalock. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIG. 1 PGP is

chemotactic rather than chemokinetic, whereas the IL-8–derived peptide SGP chemotactic at similar concentrations; PGP causes PMN superoxide production, and competitively binds CXCR1 and

CXCR2. (PDF 784 kb) SUPPLEMENTARY FIG. 2 Identification and quantification of PGP (shown as N-a-PGP here) in the BAL fluids of LPS-treated mice. (PDF 1501 kb) SUPPLEMENTARY FIG. 3 PGP is

cleared rapidly from airway fluid, is inhibited by monoclonal antibody 9A4, and causes alveolar enlargement and right ventricular hypertrophy in BALB/c mice. (PDF 716 kb) RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Weathington, N., van Houwelingen, A., Noerager, B. _et al._ A novel peptide CXCR ligand derived from extracellular

matrix degradation during airway inflammation. _Nat Med_ 12, 317–323 (2006). https://doi.org/10.1038/nm1361 Download citation * Received: 19 September 2005 * Accepted: 27 December 2005 *

Published: 12 February 2006 * Issue Date: 01 March 2006 * DOI: https://doi.org/10.1038/nm1361 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content:

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