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Hypoxia and tissue destruction in pulmonary TB.

Belton, M; Brilha, S; Manavaki, R; Mauri, F; Nijran, K; Hong, YT; Patel, NH; Dembek, M; Tezera, L; Green, J; et al. Belton, M; Brilha, S; Manavaki, R; Mauri, F; Nijran, K; Hong, YT; Patel, NH; Dembek, M; Tezera, L; Green, J; Moores, R; Aigbirhio, F; Al-Nahhas, A; Fryer, TD; Elkington, PT; Friedland, JS (2016) Hypoxia and tissue destruction in pulmonary TB. Thorax, 71 (12). pp. 1145-1153. ISSN 1468-3296 https://doi.org/10.1136/thoraxjnl-2015-207402
SGUL Authors: Friedland, Jonathan Samuel

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Abstract

BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

Item Type: Article
Additional Information: 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/
Keywords: Tuberculosis, Adult, Biopsy, Cell Hypoxia, Cells, Cultured, Collagenases, Epithelial Cells, Female, Gene Expression Regulation, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Lung, Macrophages, Male, Matrix Metalloproteinase 1, Microscopy, Confocal, Middle Aged, Mycobacterium tuberculosis, Positron Emission Tomography Computed Tomography, RNA, Messenger, Respiratory Mucosa, Tuberculosis, Pulmonary, Up-Regulation, Young Adult, Lung, Respiratory Mucosa, Cells, Cultured, Macrophages, Epithelial Cells, Humans, Mycobacterium tuberculosis, Tuberculosis, Pulmonary, Collagenases, RNA, Messenger, Microscopy, Confocal, Biopsy, Cell Hypoxia, Gene Expression Regulation, Up-Regulation, Adult, Middle Aged, Female, Male, Hypoxia-Inducible Factor 1, alpha Subunit, Matrix Metalloproteinase 1, Young Adult, Positron Emission Tomography Computed Tomography, Science & Technology, Life Sciences & Biomedicine, Respiratory System, REGULATES MATRIX METALLOPROTEINASE-1, POSITRON-EMISSION-TOMOGRAPHY, NF-KAPPA-B, MYCOBACTERIUM-TUBERCULOSIS, TNF-ALPHA, GRANULOMAS, CELLS, FLUOROMISONIDAZOLE, HIF-1-ALPHA, CAVITATION, 1103 Clinical Sciences, Respiratory System
Journal or Publication Title: Thorax
ISSN: 1468-3296
Language: eng
Dates:
DateEvent
December 2016Published
13 May 2016Published Online
24 March 2016Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
093875Wellcome Trusthttp://dx.doi.org/10.13039/100004440
G0802271Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G1000183Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 27245780
Web of Science ID: WOS:000389338200013
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110602
Publisher's version: https://doi.org/10.1136/thoraxjnl-2015-207402

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