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This Article Full Text Full Text (PDF) All Versions of this Article: fj.07-096230v1 22/9/3403    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by van Houwelingen, A. H. Articles by Folkerts, G. PubMed PubMed Citation Articles by van Houwelingen, A. H. Articles by Folkerts, G.

Induction of lung emphysema is prevented by L-arginine-threonine-arginine

Anneke H. van Houwelingen^*,1, Nathaniel M. Weathington, Vivienne Verweij^*, J. Edwin Blalock, Frans P. Nijkamp^* and Gert Folkerts^*

^* Division of Pharmacology and Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands; and

Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama, USA

¹Correspondence: Division of Pharmacology and Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 800 82, 3508 TB Utrecht, The Netherlands. E-mail: a.h.vanhouwelingen{at}uu.nl

In patients with chronic obstructive pulmonary disease (COPD), an inflammatory process is ongoing in the lungs, with concomitant damage of the alveolar structures and loss of airway function. In this inflammatory process, extracellular matrix degradation is observed. During this lung matrix degradation, small peptide fragments consisting of proline and glycine repeats generated from collagen fibers are liberated from the matrix by matrix metalloproteinases. Chemotactic activities of these collagen-derived peptides such as N-acetyl-proline-glycine-proline (PGP) via CXCR1 and CXCR2 have been reported. We show here that PGP induces neutrophil migration in vivo, which is dose dependent. Moreover, PGP is involved in the development of emphysema-like changes in the airways. The complementary peptide, L-arginine-threonine-arginine (RTR), has been shown to bind to PGP sequences and inhibit neutrophil infiltration. We show that RTR impedes both PGP- and interleukin-8-induced chemotaxis in vitro. In vivo, RTR prevents both migration and activation of neutrophils induced by PGP. Furthermore, RTR completely inhibits PGP-induced lung emphysema, assessed by changes in alveolar enlargement and right ventricular hypertrophy. In conclusion, these data indicate that collagen breakdown products, especially PGP, are important in the pathogenesis of COPD and that PGP antagonism via RTR ameliorates lung emphysema.—van Houwelingen, A. H., Weathington, N. M., Verweij, V., Blalock, J. E., Nijkamp, F. P., Folkerts, G. Induction of lung emphysema is prevented by L-arginine-threonine-arginine.

Key Words: collagen breakdown • COPD • chemotaxis • neutrophil • inflammation