Breakdown of collagen releases a tripeptide, PGP, that is chemotactic for neutrophils (PMN) in vitro. It is shown here that airway exposure to PGP causes a robust, exclusive influx of PMN, cells critical in respiratory pathology. Chronic airway exposure to this peptide recapitulates certain aspects of airway disease. Furthermore, using mass spectrometry, PGP is found in the airways of animals acutely exposed to aerosolized endotoxin and contributes to PMN chemotactic activity. The PMN chemotactic activity of PGP may be due to a marked structural relatedness to a receptor binding domain of CXC chemokines specific for PMN such as IL-8, which contain this collagen sequence or a close analog. An antagonist developed by our laboratory, termed RTR, binds PGP in solution and blocks its in vitro and in vivo effects. Likely as a result of shared structure with PGP, RTR also blocks IL-8 activity. Thus the overall goals of this proposal are to: 1) characterize the activity of PGP on PMN; 2) determine if PGP's effects are mediated through actions on chemokine receptors; and 3) determine whether PGP or a related molecule is generated in vivo and signals PMN in animal models of environmentally mediated airway inflammation like ozone exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30ES013874-03
Application #
7217286
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Humble, Michael C
Project Start
2005-04-01
Project End
2007-06-02
Budget Start
2007-04-01
Budget End
2007-06-02
Support Year
3
Fiscal Year
2007
Total Cost
$12,239
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Weathington, Nathaniel M; van Houwelingen, Anneke H; Noerager, Brett D et al. (2006) A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med 12:317-23