A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation.
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 inflammatory diseases.
Department of Physiology and Biophysics, University of Alabama at Birmingham, 1918 University Boulevard, Birmingham, Alabama 35294, USA.
Nathaniel M
NM
Weathington
Anneke H
AH
van Houwelingen
Brett D
BD
Noerager
Patricia L
PL
Jackson
Aletta D
AD
Kraneveld
F Shawn
FS
Galin
Gert
G
Folkerts
Frans P
FP
Nijkamp
J Edwin
JE
Blalock
D000818:Animals; D018893:Bronchoalveolar Lavage; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology; D019707:Receptors, Chemokine / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D040681:Structural Homology, Protein
D008024:Ligands; D008070:Lipopolysaccharides; C428643:N-acetyl-proline-glycine-proline; D009842:Oligopeptides; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B