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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    • "Inflamed tissues are usually characterized by inflammatory hypoxia owing to increased metabolism and low levels of oxygen and glucose in the inflamed region89909192. In fact, HIF mediated pathways are closely involved in numerous human diseases including inflammatory bowel disease, Crohn's disease, acute lung injury, and infectious diseases [89,90]. Oxygen deprivation under hypoxia and pro-inflammatory molecules can stabilize HIF-1α in the inflamed region, and hypoxia per se can be an inflammatory stimulus by enhancing pro-inflammatory cytokines. "
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    ABSTRACT: Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are members of the 2-oxoglutarate dependent non-heme iron dioxygenases. Due to their physiological roles in regulation of HIF-1α stability, many efforts have been focused on searching for selective PHD inhibitors to control HIF-1α levels for therapeutic applications. In this review, we first describe the structure of PHD2 as a molecular basis for structure-based drug design (SBDD) and various experimental methods developed for measuring PHD activity. We further discuss the current status of the development of PHD inhibitors enabled by combining SBDD approaches with high-throughput screening. Finally, we highlight the clinical implications of small molecule PHD inhibitors.
    Preview · Article · Nov 2015 · Molecules
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    • "Besides this posttranscriptional and oxygendependent HIF regulation, there are other mechanisms of HIF regulation at a transcriptional level that are oxygenindependent and work under inflammatory, infectious, or oxidative stress conditions [31]. In this sense, how bacterial lipopolysaccharide (LPS), a cell membrane component of Gram-negative bacteria, can increase HIF-1í µí»¼ transcription has been previously shown [32]. "
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) has become a major health issue in western countries in parallel with the dramatic increase in the prevalence of obesity and all obesity related conditions, including respiratory diseases as obstructive sleep apnea-hypopnea syndrome (OSAHS). Interestingly, the severity of the liver damage in obesity-related NAFLD has been associated with the concomitant presence of OSAHS. In the presence of obesity, the proinflammatory state in these patients together with intermittent episodes of hypoxia, characteristic of OSAHS pathogenesis, may lead to an enhanced inflammatory response mediated by a positive feedback loop mechanism that implicates HIF-1 and NF κ B. Thus, the severity of liver involvement in obese NAFLD patients with a concomitant diagnosis of OSAHS could be explained. In this review, we focus on the molecular mechanisms underlying the hepatic response to chronic intermittent hypoxia and its interaction with innate immunity in obesity-related NAFLD.
    Full-text · Article · Sep 2015 · BioMed Research International
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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.
    Full-text · Article · Jul 2015 · Biochimica et Biophysica Acta
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