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Interstitial lung disease
Original article
Deficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis
  1. Emmet E McGrath1,
  2. Allan Lawrie2,
  3. Helen M Marriott1,
  4. Paul Mercer3,
  5. Simon S Cross4,
  6. Nadine Arnold2,
  7. Vanessa Singleton1,
  8. Alfred A R Thompson1,
  9. Sarah R Walmsley1,
  10. Stephen A Renshaw1,
  11. Ian Sabroe1,
  12. Rachel C Chambers3,
  13. David H Dockrell2,
  14. Moira K B Whyte1
  1. 1Department of Infection and Immunity, University of Sheffield, Sheffield, UK
  2. 2Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
  3. 3Centre for Respiratory Research, University College, London, UK
  4. 4Department of Neuroscience, University of Sheffield, Sheffield, UK
  1. Correspondence to Professor Moira Whyte, Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK; m.k.whyte{at}sheffield.ac.uk

Abstract

Background The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF.

Methods TRAIL−/− and wild-type mice were instilled with bleomycin and inflammation assessed at various time points by bronchoalveolar lavage and histology. Collagen deposition was measured by tissue hydroxyproline content. TRAIL expression in human IPF lung samples was assessed by immunohistochemistry and peripheral blood TRAIL measured by ELISA.

Results TRAIL−/− mice had an exaggerated delayed inflammatory response to bleomycin, with increased neutrophil numbers (mean 3.19±0.8 wild type vs 11.5±5.4×104 TRAIL−/−, p<0.0001), reduced neutrophil apoptosis (5.42±1.6% wild type vs 2.47±0.5% TRAIL−/−, p=0.0003) and increased collagen (3.45±0.2 wild type vs 5.8±1.3 mg TRAIL−/−, p=0.005). Immunohistochemical analysis showed induction of TRAIL in bleomycin-treated wild-type mice. Patients with IPF demonstrated lower levels of TRAIL expression than in control lung biopsies and their serum levels of TRAIL were significantly lower compared with matched controls (38.1±9.6 controls vs 32.3±7.2 pg/ml patients with IPF, p=0.002).

Conclusion These data suggest TRAIL may exert beneficial, anti-inflammatory actions in chronic pulmonary inflammation in murine models and that these mechanisms may be compromised in human IPF.

  • Neutrophil
  • apoptosis
  • death ligand
  • bleomycin
  • cytokine biology
  • innate immunity
  • interstitial fibrosis
  • primary pulmonary hypertension
  • bacterial infection
  • lymphocyte biology
  • macrophage biology
  • pneumonia
  • respiratory infection
  • neutrophil biology
  • histology/cytology
  • COPD mechanisms
  • allergic lung disease
  • asthma
  • eosinophil biology
  • allergic alveolitis
  • lung proteases
  • sarcoidosis

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

https://doi.org/10.1136/thoraxjnl-2011-200863

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    Footnotes

    • Funding This work was funded by a Wellcome Trust Clinical Research Training Fellowship to EMcG (075776), by the NIHR Cardiovascular Biomedical Research Unit Sheffield (IS and MKBW) and by generous donations in memory of Mrs Eileen Hawley, Mrs Susan Utley and Mr Derrick Woolley. AL holds an MRC Career Development Award Fellowship (G0800318), SRW is a Wellcome Clinician Scientist Fellow (078244), SAR is an MRC Senior Clinical Fellow (G0701932) and DHD a Wellcome Trust Senior Clinical Fellow (076945).

    • Competing interests None.

    • Ethics approval Ethics approval was provided by Papworth Hospital Ethics Committee and South Sheffield Research Ethics Committee.

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