Hypoxia and tissue destruction in pulmonary TB

Abstract

BackgroundIt 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).MethodsWe 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.ConclusionsHuman TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis

“…During pulmonary TB disease in humans, the presence of caseum-filled hypoxic necrotic granulomas in the lungs is associated with severe disease, facilitating bacterial spread and compromising lung integrity. Human pulmonary TB lesions are hypoxic (5), and as a result, matrix metalloproteases such as MMP-1 associated with tissue remodeling are upregulated (5). Previous studies have shown that animal models of TB (e.g., rabbit, guinea pig, and nonhuman primate) develop heterogeneous granulomas, wherein hypoxia is closely associated with necrotic granulomas as opposed to solid granulomas (6).…”

Review of the British Thoracic Society Winter Meeting 2016, 7–9 December, London, UK

“…Professor Friedland's group (London) used positron emission tomography (PET) scans with the hypoxic-specific tracer ( 18 F-labelled fluoromisonidazole), to show for the first time that pulmonary TB lesions are severely hypoxic and that hypoxia upregulates the collagenase matrix metalloproteinase-1, an important contributor to the cavitation and lung destruction seen in this disease 7. This was followed by Professor Lederer (New York, USA), who showed that higher levels of rheumatoid arthritis (RA) autoantibodies, even in the absence of clinically evident RA, are associated with subclinical interstitial lung disease (ILD) on CT imaging, particularly in smokers.…”

Cytokine diagnosis of pleural TB: will it stand the test of time?

“…Advanced pulmonary TB is characterised by tissue destruction, hypoxia and cavitation,9 with high bacterial loads within the cavity wall,10 whereas pleural TB has a relatively low bacterial load with extensive fluid collection 11. Consequently, pleural fluid culture is positive in fewer than 50% of cases 12.…”