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Respiratory research
Original article
Evidence for chemokine synergy during neutrophil migration in ARDS
  1. Andrew E Williams1,
  2. Ricardo J José1,
  3. Paul F Mercer1,
  4. David Brealey2,
  5. Dhruv Parekh3,
  6. David R Thickett3,
  7. Cecelia O'Kane4,
  8. Danny F McAuley4,
  9. Rachel C Chambers1
  1. 1Division of Medicine, Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Institute, University College London (UCL), London, UK
  2. 2Bloomsbury Institute of Intensive Care Medicine, University College Hospital, London, UK
  3. 3Institute of Inflammation and Aging, University of Birmingham, Birmingham, UK
  4. 4Centre for Experimental Medicine, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University of Belfast and Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK
  1. Correspondence to Professor Rachel C Chambers, Centre for Inflammation and Tissue Repair, Rayne Institute, Division of Medicine, University College London (UCL), London WC1E 6JF, UK; r.chambers{at}ucl.ac.uk

Abstract

Background Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterised by pulmonary oedema, respiratory failure and severe inflammation. ARDS is further characterised by the recruitment of neutrophils into the lung interstitium and alveolar space.

Objectives The factors that regulate neutrophil infiltration into the inflamed lung and our understanding of the pathomechanisms in ARDS remain incomplete. This study aimed at determining the role of the chemokine (C-C motif) ligand (CCL)2 and CCL7 in ARDS.

Methods CCL2 and CCL7 protein levels were measured in bronchoalveolar lavage (BAL) fluid obtained from lipopolysaccharide(LPS)-challenged human volunteers and two separate cohorts of patients with ARDS. Neutrophil chemotaxis to ARDS BAL fluid was evaluated and the contribution of each was assessed and compared with chemokine (C-X-C motif) ligand 8 (CXCL8). Chemokine receptor expression on neutrophils from blood or BAL fluid of patients with ARDS was analysed by flow cytometry.

Results CCL2 and CCL7 were significantly elevated in BAL fluid recovered from LPS-challenged volunteers and patients with ARDS. BAL fluid from patients with ARDS was highly chemotactic for human neutrophils and neutralising either CCL2 or CCL7 attenuated the neutrophil chemotactic response. Moreover, CCL2 and CCL7 synergised with CXCL8 to promote neutrophil migration. Furthermore, neutrophils isolated from the blood or BAL fluid differentially regulated the cell surface expression of chemokine (C-X-C motif) receptor 1 and C-C chemokine receptor type 2 during ARDS.

Conclusion This study highlights important inflammatory chemokines involved in regulating neutrophil migration, which may have potential value as therapeutic targets for the treatment of ARDS.

  • Cytokine Biology
  • Innate Immunity
  • Neutrophil Biology
  • ARDS

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/thoraxjnl-2016-208597

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    Footnotes

    • AEW and RJJ contributed equally.

    • Correction notice This article has been corrected since it was published Online First. The last sentence in figure 4 has been corrected. The section ‘..one-way analysis of variance with Newman-Keuls’ has been replace with ‘a Wilcoxon signed rank test’.

    • Twitter Follow Andrew Williams at @AndrewEWilliams

    • Contributors AEW and RJJ participated in experimental design, performed experiments and assays. AEW drafted the manuscript. RJJ collected and processed patient samples. PFM participated in experimental design and edited the manuscript. DRT, DP, DFMcA, COK and DB collected patient samples and edited the manuscript. RCC participated in experimental design, evaluated data and drafted the manuscript.

    • Funding This work was supported by funding from the Wellcome Trust (097216/z/11/z), the Rosetrees Trust, the Medical Research Council UK (G0800265),UCL Business (POC-12-024 and the National Institute for Health Research University College London Hospitals Biomedical Research Centre grant (BRC76/HI/RC).

    • Competing interests RCC, PFM and AEW have filed a patent on CCL7 as a novel drug target in ARDS (PCT/GB2013/050665).

    • Patient consent Obtained.

    • Ethics approval London-South East Research Ethics Committee (ref: 13/LO/274).

    • Provenance and peer review Not commissioned; externally peer reviewed.

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