Hypoxia and inflammation. N Engl J Med

Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045, USA.
New England Journal of Medicine (Impact Factor: 55.87). 02/2011; 364(7):656-65. DOI: 10.1056/NEJMra0910283
Source: PubMed
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    • "Further analysis is required to elucidate the mechanism(s) of this effect. It is postulated that tissue hypoxia and inflammation are mutually regulated [77]. Hypoxia triggers vascular leakage and edema, activates pro-inflammatory signalling and infiltration, and stimulates expression of toll-like receptors and apoptosis, thus promoting inflammation. "
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    ABSTRACT: Abnormal accumulation of oncometabolite fumarate and succinate is associated with inhibition of mitochondrial function and carcinogenesis. By competing with α-ketoglutarate, oncometabolites also activate hypoxia inducible factors (HIF), which makes oncometabolite mimetics broadly utilised in hypoxia research. We found that dimethyloxalylglycine (DMOG), a synthetic analogue of α-ketoglutarate, commonly used to induce HIF signalling, inhibits O2 consumption in cancer cell lines HCT116 and PC12, well before activation of HIF pathways. A rapid suppression of cellular respiration was accompanied by a decrease in histone H4 lysine 16 acetylation and not abolished by double knockdown of HIF-1α and HIF-2α. In agreement with this, production of NADH and state 3 respiration in isolated mitochondria were down-regulated by the de-esterified DMOG derivative, N-oxalylglycine. Exploring the roles of DMOG as a putative inhibitor of glutamine / α-ketoglutarate metabolic axis, we found that the observed suppression of OxPhos and compensatory activation of glycolytic ATP flux make cancer cells vulnerable to combined treatment with DMOG and inhibitors of glycolysis. On the other hand, DMOG treatment impairs deep cell deoxygenation in 3D tissue culture models, demonstrating a potential to relieve functional stress imposed by deep hypoxia on tumour, ischemic or inflamed tissues. Indeed, using a murine model of colitis, we found that O2 availability in the inflamed colon tissue rapidly increased after application of DMOG, which could contribute to the known therapeutic effect of this compound. Overall, our results provide new insights into the relationship between mitochondrial function, O2 availability, metabolic reprogramming and associated diseases. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 07/2015; 1847(10). DOI:10.1016/j.bbabio.2015.06.016 · 4.66 Impact Factor
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    • "Hypoxia has two effects on tumor cells: 1-necrosis of cells in the inner region of the tumor, more distant from host tissue vessels. 2- adaptation of cells to the hypoxic gradient within the tumor through the activation of HIF1α and expression of many genes such as VEGF (which is important in tumor neoangiogenesis), Glut1 and HKII (which explain the metabolic remodeling of malignant tumors) and RAGE, P2X7, Toll-like, etc. (alarmin receptors) (Fig. 1) [1] [7] [8] [11] [20] [24] [40] [41] [42] [43] [44] [45] [46]. Importantly, necrotic cells release alarmins (HMGB1, ATP/ADP, membrane debris, nucleic acids, etc.) that, by binding to their receptors, activate NFkB and hundreds of genes of the inflammatory reparative response (IRR) (Fig. 1) [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60]. "
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    ABSTRACT: Hypoxia and Inflammation are strictly interconnected with important consequences at clinical and therapeutic level. While cell and tissue damage due to acute hypoxia mostly leads to cell necrosis, in chronic hypoxia, cells that are located closer to vessels are able to survive adapting their phenotype through the expression of a number of genes, including proinflammatory receptors for alarmins. These receptors are activated by alarmins released by necrotic cells and generate signals for master transcription factors such as NFkB, AP1, etc. which control hundreds of genes for innate immunity and damage repair. Clinical consequences of chronic inflammatory reparative response activation include cell and tissue remodeling, damage in the primary site and, the systemic involvement of distant organs and tissues. Thus every time a tissue environment become stably hypoxic, inflammation can be activated followed by chronic damage and cell death or repair with vessel proliferation and fibrosis. This pathway can occur in cancer, myocardial infarction and stroke, diabetes, obesity, neurodegenerative diseases, chronic and autoimmune diseases and age-related diseases. Interestingly, proinflammatory gene expression can be observed earlier in hypoxic tissue cells and, in addition, in activated resident or recruited leukocytes. Herewith, the reciprocal relationships between hypoxia and inflammation will be shortly reviewed to underline the possible therapeutic targets to control hypoxia-related inflammation in a number of epidemiologically important human diseases and conditions.
    03/2015; 15(3). DOI:10.2174/1871530315666150316120112
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    • "There is growing evidence that inflammatory processes are involved in all stages of the ischemic cascade, from the early intravascular events after arterial occlusion to the late regenerative alterations leading to brain damage and tissue repair (Iadecola and Anrather, 2011). Immediately after interruption of blood supply, reactive oxygen species (ROS) trigger the coagulation cascade and lead to the activation of complement (i.e., complement C3), platelet and endothelial cells (Eltzschig and Carmeliet, 2011; Peerschke et al., 2010; Song et al., 2006). Proinflammatory mediators such as cytokines and chemokines are rapidly Experimental Neurology 265 (2015) 142–151 Abbreviations: OH-F, fullerenol; GlcN, glucosamine; GlcN-F, glucosamine fullerene; WKY, Wistar-Kyoto-rats; SHR, spontaneously hypertensive rats; tMCAO, transient middle cerebral artery occlusion; TLR-4, toll-like receptor 4; IL-1 β, interleukin 1 β; TNF-α, tumor necrosis factor-α; NF-κB, nuclear factor kappaB; STAIR, Stroke Therapy Academic Industry Roundtable; MRI, magnetic resonance imaging; qRT PCR, quantitative real-time PCR. "
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    ABSTRACT: Cerebral inflammation plays a crucial role in the pathophysiology of ischemic stroke and is involved in all stages of the ischemic cascade. Fullerene derivatives, such as fullerenol (OH-F) are radical scavengers acting as neuroprotective agents while glucosamine (GlcN) attenuates cerebral inflammation after stroke. We created novel glucosamine–fullerene conjugates (GlcN-F) to combine their protective effects and compared them to OH-F regarding stroke-induced cerebral inflammation and cellular damage. Fullerene derivatives or vehicle was administered intravenously in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) immediately after transient middle cerebral artery occlusion (tMCAO). Infarct size was determined at day 5 and neurological outcome at days 1 and 5 after tMCAO. CD68- and NeuN-staining were performed to determine immunoreactivity and neuronal survival respectively. Cytokine and toll like receptor 4 (TLR-4) expression was assessed using quantitative real-time PCR. Magnetic resonance imaging revealed a significant reduction of infarct volume in both, WKY and SHR that were treated with fullerene derivatives. Treated rats showed an amelioration of neurological symptoms as both OH-F and GlcN-F prevented neuronal loss in the perilesional area. Cerebral immunoreactivity was reduced in treated WKY and SHR. Expression of IL-1β and TLR-4 was attenuated in OH-F-treated WKY rats. In conclusion, OH-F and GlcN-F lead to a reduction of cellular damage and inflammation after stroke, rendering these compounds attractive therapeutics for stroke.
    Experimental Neurology 01/2015; accepted. DOI:10.1016/j.expneurol.2015.01.005 · 4.70 Impact Factor
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