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Hypoxia and tissue destruction in pulmonary TB

Hypoxia and tissue destruction in pulmonary TB
Hypoxia and tissue destruction in pulmonary TB
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.
0040-6376
1145-1153
Belton, M.
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Brilha, S.
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Manavaki, R.
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Mauri, F.
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Nijran, K.
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Hong, Y.T.
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Patel, N.
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Dembek, M.
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Tezera, L.
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Green, J.
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Moores, R.
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Aigbirhio, F.
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Al-Nahtas, A.
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Fryer, T.D.
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Elkington, P.
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Friedland, J.S.
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Belton, M.
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Brilha, S.
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Manavaki, R.
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Mauri, F.
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Nijran, K.
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Hong, Y.T.
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Patel, N.
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Dembek, M.
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Tezera, L.
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Green, J.
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Moores, R.
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Aigbirhio, F.
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Al-Nahtas, A.
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Fryer, T.D.
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Elkington, P.
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Friedland, J.S.
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Belton, M., Brilha, S., Manavaki, R., Mauri, F., Nijran, K., Hong, Y.T., Patel, N., Dembek, M., Tezera, L., Green, J., Moores, R., Aigbirhio, F., Al-Nahtas, A., Fryer, T.D., Elkington, P. and Friedland, J.S. (2016) Hypoxia and tissue destruction in pulmonary TB. Thorax, 71 (12), 1145-1153. (doi:10.1136/thoraxjnl-2015-207402). (In Press)

Record type: Article

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.

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Accepted/In Press date: 28 March 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 393446
URI: https://eprints.soton.ac.uk/id/eprint/393446
ISSN: 0040-6376
PURE UUID: 74ecd74d-d44f-4fa1-b836-a086a9fb9fe0
ORCID for L. Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for P. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 27 Apr 2016 08:56
Last modified: 10 Dec 2019 01:37

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Contributors

Author: M. Belton
Author: S. Brilha
Author: R. Manavaki
Author: F. Mauri
Author: K. Nijran
Author: Y.T. Hong
Author: N. Patel
Author: M. Dembek
Author: L. Tezera ORCID iD
Author: J. Green
Author: R. Moores
Author: F. Aigbirhio
Author: A. Al-Nahtas
Author: T.D. Fryer
Author: P. Elkington ORCID iD
Author: J.S. Friedland

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