Peer Reviewed

1

Document Type

Article

Publication Date

1-2-2015

Keywords

cystic fibrosis, CXCL8, decoy molecule

Funder/Sponsor

Program for Research in Third Level Institutes (PRTLI)

Comments

The original article is available at http://www.sciencedirect.com/science/article/pii/S0161589014002788

Abstract

BACKGROUND: The chemokine interleukin-8 (CXCL8) is a key mediator of inflammation in airways of patients with cystic fibrosis (CF). Glycosaminoglycans (GAGs) possess the ability to influence the chemokine profile of the CF lung by binding CXCL8 and protecting it from proteolytic degradation. CXCL8 is maintained in an active state by this glycan interaction thus increasing infiltration of immune cells such as neutrophils into the lungs. As the CXCL8-based decoy PA401 displays no chemotactic activity, yet demonstrates glycan binding affinity, the aim of this study was to investigate the anti-inflammatory effect of PA401 on CXCL8 levels, and activity, in CF airway samples in vitro.

METHODS: Bronchoalveolar lavage fluid (BALF) was collected from patients with CF homozygous for the ΔF508 mutation (n=13). CXCL8 in CF BALF pre and post exposure to PA401 was quantified by ELISA. Western blot analysis was used to determine PA401 degradation in CF BALF. The ex vivo chemotactic activity of purified neutrophils in response to CF airway secretions was evaluated post exposure to PA401 by use of a Boyden chamber-based motility assay.

RESULTS: Exposure of CF BALF to increasing concentrations of PA401 (50-1000pg/ml) over a time course of 2-12h in vitro, significantly reduced the level of detectable CXCL8 (P

CONCLUSION: PA401 can disrupt CXCL8:GAG complexes, rendering the chemokine susceptible to proteolytic degradation. Clinical application of a CXCL8 decoy, such as PA401, may serve to decrease the inflammatory burden in the CF lung in vivo.

Disciplines

Medicine and Health Sciences

Citation

McElvaney OJ, O'Reilly N, White M, Lacey N, Pohl K, Gerlza T, Bergin DA, Kerr H, McCarthy C, O'Brien ME, Adage T, Kungl AJ, Reeves EP, McElvaney NG. The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis. Molecular Immunology. 2015 Feb;63(2):550-8. doi: 10.1016/j.molimm.2014.10.013.

PubMed ID

25453468

DOI Link

10.1016/j.molimm.2014.10.013

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