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Lookup NU author(s): Dr Lee Borthwick, Dr Rahul Mahida, Andrew Walker, Aaron Gardner, Wona Suwara, Dr Elizabeth Moisey, Dr Malcolm Brodlie, Professor Christopher WardORCiD, Dr John Perry, Professor Anthony De SoyzaORCiD, Professor Derek Mann, Professor Andrew FisherORCiD
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Bronchiolitis obliterans syndrome is characterized by fibrotic obliteration of small airways which severely impairs graft function and survival after lung transplantation. Bronchial epithelial cells from the transplanted lung can undergo epithelial to mesenchymal transition and this can be accentuated by activated macrophages. Macrophages demonstrate significant plasticity and change phenotype in response to their microenvironment. In this study we aimed to identify secretory products from macrophages that might be therapeutic targets for limiting the inflammatory accentuation of epithelial to mesenchymal transition in bronchiolitis obliterans syndrome. TNFα, IL-1β and IL-8 are elevated in bronchoalveolar lavage from lung transplant patients prior to diagnosis of bronchiolitis obliterans syndrome. Classically activated macrophages secrete more TNFα and IL-1β than alternatively activated macrophages and dramatically accentuate TGF-β1-driven epithelial to mesenchymal transition in bronchial epithelial cells isolated from lung transplant patients. Blocking TNFα, but not IL-1β, inhibits the accentuation of epithelial to mesenchymal transition. In a pilot unblinded therapeutic intervention in five patients with progressive bronchiolitis obliterans syndrome, anti-TNFα treatment improved forced expiratory volume in 1 second and 6-min walk distances in four patients. Our data identify TNFα as a potential new therapeutic target in bronchiolitis obliterans syndrome deserving of a randomized placebo controlled clinical trial.
Author(s): Borthwick LA, Corris PA, Mahida R, Walker A, Gardner A, Suwara M, Johnson GE, Moisey EJ, Brodlie M, Ward C, Perry JD, de Soyza A, Mann DA, Fisher AJ
Publication type: Article
Publication status: Published
Journal: American Journal of Transplantation
Year: 2013
Volume: 13
Issue: 3
Pages: 621-633
Print publication date: 17/01/2013
ISSN (print): 1600-6135
ISSN (electronic): 1600-6143
Publisher: Wiley-Blackwell Publishing, Inc.
URL: http://dx.doi.org/10.1111/ajt.12065
DOI: 10.1111/ajt.12065
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