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TNFα From Classically Activated Macrophages Accentuates Epithelial to Mesenchymal Transition in Obliterative Bronchiolitis

Lookup NU author(s): Dr Lee Borthwick, Professor Paul Corris, Dr Rahul Mahida, Andrew Walker, Aaron Gardner, Wona Suwara, Dr Elizabeth Moisey, Dr Malcolm Brodlie, Dr Christopher Ward, Dr John Perry, Professor Anthony De Soyza, Professor Derek Mann, Professor Andrew Fisher

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Abstract

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.


Publication metadata

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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