title: Hypoxia and tissue destruction in pulmonary TB.
abstract: 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).
  
  
  
  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.
  
  
  
  [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. InMycobacterium 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.tbinfection 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.
  
  
  
  Human TB lesions are severely hypoxic andM.tbdrives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Moerida
authors.initials: M
authors.lastname: Belton
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Brilha
authors.affiliation: Department of Radiology, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Roido
authors.initials: R
authors.lastname: Manavaki
authors.affiliation: Department of Histopathology, Hammersmith Campus, Imperial College London, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mauri
authors.affiliation: Radiological Science Unit Charing Cross Campus, Department of Nuclear Medicine, Charing Cross Campus, Imperial College NHS Trust, London, UK.
authors.forename: Kuldip
authors.initials: K
authors.lastname: Nijran
authors.affiliation: Wolfson Brain Imaging Centre, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Young T
authors.initials: YT
authors.lastname: Hong
authors.affiliation: Radiological Science Unit Charing Cross Campus, Department of Nuclear Medicine, Charing Cross Campus, Imperial College NHS Trust, London, UK.
authors.forename: Neva H
authors.initials: NH
authors.lastname: Patel
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Marcin
authors.initials: M
authors.lastname: Dembek
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Liku
authors.initials: L
authors.lastname: Tezera
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Green
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Moores
authors.affiliation: Wolfson Brain Imaging Centre, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Franklin
authors.initials: F
authors.lastname: Aigbirhio
authors.affiliation: Radiological Science Unit Charing Cross Campus, Department of Nuclear Medicine, Charing Cross Campus, Imperial College NHS Trust, London, UK.
authors.forename: Adil
authors.initials: A
authors.lastname: Al-Nahhas
authors.affiliation: Wolfson Brain Imaging Centre, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Fryer
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.|NIHR Respiratory Biomedical Research Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.affiliation: Section of Infectious Diseases and Immunity, Imperial College London, London, UK.
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
mesh_terms: D000328:Adult; D001706:Biopsy; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D018613:Microscopy, Confocal; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000502:physiology; D000072078:Positron Emission Tomography Computed Tomography; D012333:RNA, Messenger / Q000235:genetics; D020545:Respiratory Mucosa / Q000201:enzymology; D014397:Tuberculosis, Pulmonary / Q000000981:diagnostic imaging / Q000473:pathology*; D015854:Up-Regulation / Q000502:physiology; D055815:Young Adult
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017364:Collagenases; D020781:Matrix Metalloproteinase 1
keywords: Tuberculosis