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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    • "Many studies have demonstrated that hypoxia has impact on the activity of NF-í µí¼…B [27], while hypoxia-induced NF-í µí¼…B modulated the levels and activity of HIF-1í µí»¼ [24]. On the other hand, some proinflammatory cytokines (TNF-í µí»¼, IL-1, IL-6, and IL-8) and proinflammatory enzymes (cyclooxygenase- 2 (COX-2), nitric oxide synthase) are controlled by NF-í µí¼…B [27]. Also in vitro experiments have showed that hypoxic conditions increased the expression of IL-6, IL-8, COX-2, and VEGF in dental pulp cells [28]. "
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    ABSTRACT: Orthodontic force may lead to cell damage, circulatory disturbances, and vascular changes of the dental pulp, which make a hypoxic environment in pulp. In order to maintain the homeostasis of dental pulp, hypoxia will inevitably induce the defensive reaction. However, this is a complex process and is regulated by numerous factors. In this study, we established an experimental animal model of orthodontic tooth movement to investigate the effects of mechanical force on the expression of VEGF and HIF-1α in dental pulp. Histological analysis of dental pulp and expressions of HIF-1α and VEGF proteins in dental pulp were examined. The results showed that inflammation and vascular changes happened in dental pulp tissue in different periods. Additionally, there were significant changes in the expression of HIF-1α and VEGF proteins under orthodontic force. After application of mechanical load, expression of HIF-1α and VEGF was markedly positive in 1, 3, 7 d, and 2 w groups, and then it weakened in 4 w group. These findings suggested that the expression of HIF-1α and VEGF was enhanced by mechanical force. HIF-1α and VEGF may play an important role in retaining the homeostasis of dental pulp during orthodontic tooth movement.
    Mediators of Inflammation 10/2015; 2015(16):215761. DOI:10.1155/2015/215761 · 3.24 Impact Factor
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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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