Hypoxia and tissue destruction in pulmonary TB.
Hypoxia and tissue destruction in pulmonary TB.
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DOI：
10.1136/thoraxjnl-2015-207402
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发表时间：
2016-12
期刊：
影响因子：
10
通讯作者：
Friedland JS
中科院分区：
文献类型：
--
作者：
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
目前尚不清楚人类结核病的病变是否是缺氧的，或者这是否影响疾病的病理学。人TB的特征在于由宿主基质金属蛋白酶（MMP），特别是胶原酶如基质金属蛋白酶-1（MMP-1）驱动的广泛的肺破坏。我们使用示踪剂[18 F]-氟咪唑（[18 F]FMISO）和免疫组织化学研究了5例PET成像患者的组织缺氧。我们研究了正常氧、缺氧、化学缺氧和小干扰RNA（siRNA）抑制对原代人细胞培养模型系统中MMP分泌的调节。[18F]FMISO在结核实变区域和肺空洞周围积聚，首次证明人体组织严重缺氧。Patlak动态PET数据分析显示患者内部和患者之间缺氧水平不均匀。在结核分枝杆菌（M.tb）感染的人巨噬细胞中，缺氧（1%pO2）上调MMP-1基因表达170倍，驱动分泌和酪蛋白溶解活性。二甲基草酰甘氨酸（DMOG），一种稳定转录因子缺氧诱导因子（HIF）-1α的小分子抑制剂，类似地上调MMP-1。低氧不影响分枝杆菌的复制。肺结核通过细胞间网络调节低氧诱导原代呼吸道上皮细胞MMP-1表达。缺氧时，HIF-1α和NF-κB调节MMP-1活性的增加。此外，即使在常氧条件下，结核分枝杆菌感染也可驱动HIF-1α的积累。在人TB肺活检中，上皮样巨噬细胞和多核巨细胞表达HIF-1α。HIF-1α阻断，包括靶向siRNA，抑制TB驱动的MMP-1基因表达和分泌。人TB病变严重缺氧，结核分枝杆菌驱动HIF-1α积累，协同增加胶原酶活性，导致肺破坏和空洞。
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. 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. 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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影响因子：
7.3
作者：
Kuebler, Andre;Luna, Brian;Larsson, Christer;Ammerman, Nicole C.;Andrade, Bruno B.;Orandle, Marlene;Bock, Kevin W.;Xu, Ziyue;Bagci, Ulas;Molura, Daniel J.;Marshall, John;Burns, Jay;Winglee, Kathryn;Ahidjo, Bintou Ahmadou;Cheung, Laurene S.;Klunk, Mariah;Jain, Sanjay K.;Kumar, Nathella Pavan;Babu, Subash;Sher, Alan;Friedland, Jon S.;Elkington, Paul T. G.;Bishai, William R.
通讯作者：
Bishai, William R.
RSV感染期间缺氧诱导因子（HIF）-1的氧无氧稳定。
影响因子：
3.7
作者：
Haeberle, Helene A.;Duerrstein, Carin;Rosenberger, Peter;Hosakote, Yashoda M.;Kuhlicke, Johannes;Kempf, Volkhard A. J.;Garofalo, Roberto P.;Eltzschig, Holger K.
通讯作者：
Eltzschig, Holger K.
DOI：
10.1038/nri2607
发表时间：
2009-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.4
作者：
Harper, Jamie;Skerry, Ciaran;Jain, Sanjay K.
通讯作者：
Jain, Sanjay K.
影响因子：
64.8
作者：
Rius, Jordi;Guma, Monica;Karin, Michael
通讯作者：
Karin, Michael