FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2078703212> ?p ?o ?g. }

• W2078703212 endingPage "1755" @default.
• W2078703212 startingPage "1748" @default.
• W2078703212 abstract "The gastrointestinal epithelium is anatomically positioned to provide a selective barrier between the anaerobic lumen and lamina propria, which has a high rate of metabolism. Supported by a complex vasculature, this important barrier is affected by reduced blood flow and resultant tissue hypoxia, particularly during the severe metabolic shifts associated with active inflammation in individuals with inflammatory bowel disease. Activation of hypoxia-inducible factor (HIF) under these conditions promotes resolution of inflammation in mouse models of disease. Protective influences of HIF are attributed, in part, to the complex regulation of barrier protection with the intestinal mucosa. Reagents that activate HIF, via inhibition of the prolyl hydroxylase enzymes, might be developed to induce hypoxia-mediated resolution in patients with intestinal mucosal inflammatory disease. The gastrointestinal epithelium is anatomically positioned to provide a selective barrier between the anaerobic lumen and lamina propria, which has a high rate of metabolism. Supported by a complex vasculature, this important barrier is affected by reduced blood flow and resultant tissue hypoxia, particularly during the severe metabolic shifts associated with active inflammation in individuals with inflammatory bowel disease. Activation of hypoxia-inducible factor (HIF) under these conditions promotes resolution of inflammation in mouse models of disease. Protective influences of HIF are attributed, in part, to the complex regulation of barrier protection with the intestinal mucosa. Reagents that activate HIF, via inhibition of the prolyl hydroxylase enzymes, might be developed to induce hypoxia-mediated resolution in patients with intestinal mucosal inflammatory disease. View Large Image Figure ViewerDownload Hi-res image Download (PPT) The gastrointestinal (GI) tract constitutes the largest mucosal surface found in multicellular organisms. Intestinal epithelia line the entire GI tract, covering an area of some 300 m2 in adult humans. This monolayer of cells comprises a highly dynamic barrier that must be intricately regulated to accommodate fluid and nutrient transport and to exclude antigenic material at the luminal interface.1Laukoetter M.G. Nava P. Nusrat A. Role of the intestinal barrier in inflammatory bowel disease.World J Gastroenterol. 2008; 14: 401-407Crossref PubMed Scopus (210) Google Scholar, 2Turner J.R. Intestinal mucosal barrier function in health and disease.Nat Rev Immunol. 2009; 9: 799-809Crossref PubMed Scopus (2230) Google Scholar As such, the intestinal mucosa has a unique, adaptive metabolic profile that is regulated by many sources (eg, enteric microbiota, intestinal perfusion, and tissue oxygenation) and is subject to profound fluctuations even under physiologic, steady-state conditions.3Colgan SP, Taylor CT. Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol;7:281-287.Google Scholar For instance, marked increases in intestinal blood flow following food ingestion significantly shift local oxygen partial pressure. This metabolic profile is altered under conditions of active inflammation, such as those characterized in inflammatory bowel disease (IBD). Recent studies have associated hypoxia-regulated pathways with barrier function in patients with IBD; these pathways might help resolve mucosal inflammation. We review hypoxia-regulated pathways and discuss the therapeutic potential of modifying hypoxic signaling in patients with IBD. Intestinal mucosae are characterized by a uniquely dynamic oxygenation profile; they undergo multiple, large fluctuations in blood perfusion and metabolism per day. Even in the basal state, the component epithelial cells that line the mucosa exist in a relatively low oxygen-tension environment, described as “physiologic hypoxia.” In the small intestine, this has been attributed to a countercurrent oxygen exchange mechanism, whereby oxygen from arterial blood that supplies the villi diffuses to adjacent venules, travelling from villous tip to base, resulting in graded hypoxia.4Shepherd A.P. Metabolic control of intestinal oxygenation and blood flow.Fed Proc. 1982; 41: 2084-2089PubMed Google Scholar However, a steep oxygen gradient has also been documented in more distal, colonic regions of the GI tract, spanning from the anaerobic lumen, across the epithelium, to the richly vascularized subepithelial mucosa. Because of the high energy requirements of the GI tract and the integral role of the epithelium in maintaining intestinal homeostasis, these cells have evolved many molecular mechanisms to regulate the challenging metabolic conditions. The intestinal epithelium is remarkably resistant to hypoxia; even low levels of oxygenation within this cell layer can be altered to regulate barrier function and integrity.5Furuta G.T. Turner J.R. Taylor C.T. et al.Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.J Exp Med. 2001; 193: 1027-1034Crossref PubMed Scopus (331) Google Scholar A role for epithelial barrier dysregulation in IBD is supported by observations of increased intestinal permeability in a subset of first-degree relatives of patients with Crohn's disease (CD).6Hollander D. Vadheim C.M. Brettholz E. et al.Increased intestinal permeability in patients with Crohn's disease and their relatives A possible etiologic factor.Ann Intern Med. 1986; 105: 883-885Crossref PubMed Scopus (624) Google Scholar Barrier function of the epithelial monolayer is mediated by a number of specialized anatomic features that confer selective permeability to luminal contents.1Laukoetter M.G. Nava P. Nusrat A. Role of the intestinal barrier in inflammatory bowel disease.World J Gastroenterol. 2008; 14: 401-407Crossref PubMed Scopus (210) Google Scholar Epithelia are polarized, with apical surface functions optimized for luminal interaction and enteric bacterial exclusion (eg, intercellular junctions, vectorial membrane transport systems, and mucus secretion) and basolateral surfaces adapted for interface with the underlying mucosa and immune cell repertoire. Absorptive and barrier epithelial functions are regulated by oxygen.7Taylor C.T. Colgan S.P. Hypoxia and gastrointestinal disease.J Mol Med. 2007; 85: 1295-1300Crossref PubMed Scopus (231) Google Scholar Intestinal epithelia also actively participate as innate immune sensors of microbial pathogens and commensal organisms.8Clavel T. Haller D. Molecular interactions between bacteria, the epithelium, and the mucosal immune system in the intestinal tract: implications for chronic inflammation.Curr Issues Intest Microbiol. 2007; 8: 25-43PubMed Google Scholar, 9Kagnoff M.F. Eckmann L. Epithelial cells as sensors for microbial infection.J Clin Invest. 1997; 100: 6-10Crossref PubMed Scopus (264) Google Scholar In fact, a state of low-grade inflammation at the GI mucosal surface is sustained by omnipresent luminal antigens and is important for development of oral tolerance priming of the mucosal immune system should antigenic material penetrate the epithelial barrier. Studies with gnotobiotic mice have shown that the enteric microbiota influence epithelial cell metabolism, barrier function, and survival.10Madsen K. Cornish A. Soper P. et al.Probiotic bacteria enhance murine and human intestinal epithelial barrier function.Gastroenterology. 2001; 121: 580-591Abstract Full Text Full Text PDF PubMed Scopus (885) Google Scholar Increased epithelial permeability and resultant mucosal inflammation and injury underlie the pathology of IBD; improving our understanding of microenvironmental metabolic factors that influence initiation, perpetuation, and resolution of overt disease could lead to new therapeutic approaches. Large metabolic shifts occur at sites of active mucosal inflammation; nutrients and local oxygen become rapidly depleted, resulting in hypoxia, hypoglycemia, lactate accumulation, and acidosis.7Taylor C.T. Colgan S.P. Hypoxia and gastrointestinal disease.J Mol Med. 2007; 85: 1295-1300Crossref PubMed Scopus (231) Google Scholar Over the past decade, much work has focused on establishing the microenvironmental metabolic cues and signaling mechanisms for leukocyte recruitment to these sites and the metabolic consequences that ensue. Adaptive immune responses to GI tract inflammation are characterized by high rates of local T- and B-cell proliferation and requirements for large amounts of glucose, amino acids, and lipids to fuel oxidative phosphorylation.11Fox C.J. Hammerman P.S. Thompson C.B. Fuel feeds function: energy metabolism and the T-cell response.Nat Rev Immunol. 2005; 5: 844-852Crossref PubMed Scopus (642) Google Scholar, 12Kominsky DJ, Campbell EL, Colgan SP. Metabolic shifts in immunity and inflammation. J Immunol;184:4062–8.Google Scholar Unlike resident lymphocytes, however, innate immune myeloid cells such as neutrophils (polymorphonuclear cells [PMN]), macrophages, and dendritic cells must be actively recruited to inflammatory lesions.13Lewis J.S. Lee J.A. Underwood J.C. et al.Macrophage responses to hypoxia: relevance to disease mechanisms.J Leukoc Biol. 1999; 66: 889-900Crossref PubMed Scopus (312) Google Scholar Cell migration to these lesions is induced by complex cytokine, chemokine, and adhesion molecule expression. PMNs, for example, are mobilized by chemical signals generated at sites of active inflammation, such as interleukin-8, N-formylated peptides, leukotriene B4, and platelet-activating factor. Cell migration requires large amounts of energy, partly because high levels of adenosine triphosphate are required to sustain turnover of actin filaments.14Pollard T.D. Borisy G.G. Cellular motility driven by assembly and disassembly of actin filaments.Cell. 2003; 112: 453-465Abstract Full Text Full Text PDF PubMed Scopus (3248) Google Scholar Upon arrival at the inflammatory site, energy and oxygen demands of recruited cells increase to facilitate phagocytosis and microbial killing. The predominantly glycolytic form of metabolism shared by PMNs is thought to ensure their survival and function in the hypoxic, often anoxic environment of deep inflammatory foci.15Borregaard N. Herlin T. Energy metabolism of human neutrophils during phagocytosis.J Clin Invest. 1982; 70: 550-557Crossref PubMed Scopus (339) Google Scholar PMNs have unique mitochondria that maintain transmembrane potential via the glycerol-3-phosphate shuttle, which regulates aerobic glycolysis and promotes energy production.16van Raam B.J. Sluiter W. de Wit E. et al.Mitochondrial membrane potential in human neutrophils is maintained by complex III activity in the absence of supercomplex organisation.PLoS One. 2008; 3: e2013Crossref PubMed Scopus (108) Google Scholar Phagocytic functions are controlled by antimicrobial peptides, proteases, and reactive oxygen species (ROS) generated in response to bacterial engulfment.17El-Benna J. Dang P.M. Gougerot-Pocidalo M.A. Priming of the neutrophil NADPH oxidase activation: role of p47phox phosphorylation and NOX2 mobilization to the plasma membrane.Semin Immunopathol. 2008; 30: 279-289Crossref PubMed Scopus (259) Google Scholar ROS are short-lived reactive molecules derived from the incomplete reduction of oxygen, such as superoxide anion, hydrogen peroxide, and hydroxyl radical. Rapid generation of ROS by phagocytes is mediated by a powerful respiratory or oxidative burst, commensurate with large increases in oxygen and glucose consumption that in turn activate further ROS production.18Gabig T.G. Bearman S.I. Babior B.M. Effects of oxygen tension and pH on the respiratory burst of human neutrophils.Blood. 1979; 53: 1133-1139Crossref PubMed Google Scholar Upon activation, it is estimated that PMN oxygen demands increase by as much as 50-fold, eliciting consumption of up to 10 times more oxygen than any other cell in the body. The PMN oxidative burst is not inhibited by oxygen concentrations as low as 4.5%,18Gabig T.G. Bearman S.I. Babior B.M. Effects of oxygen tension and pH on the respiratory burst of human neutrophils.Blood. 1979; 53: 1133-1139Crossref PubMed Google Scholar so ROS are still generated in the hypoxic environment of intestinal inflammatory lesions. There is evidence for ROS induction in other cell types, including intestinal epithelial cells, in response to microbial signals.19Lambeth J.D. NOX enzymes and the biology of reactive oxygen.Nat Rev Immunol. 2004; 4: 181-189Crossref PubMed Scopus (2437) Google Scholar Although ROS are usually considered to be microbicidal because of their role in the phagocytic immune response, they are also important second messengers that are involved in mucosal injury in IBD.20McKenzie S.J. Baker M.S. Buffinton G.D. et al.Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease.J Clin Invest. 1996; 98: 136-141Crossref PubMed Scopus (314) Google Scholar The metabolic changes that occur during mucosal inflammation in IBD might also be studied during development of hypoxia in inflammatory lesions. The presence of hypoxia at sites of mucosal inflammation was first identified in mouse models of IBD using 2-nitroimidazole dyes,21Karhausen J. Furuta G.T. Tomaszewski J.E. et al.Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis.J Clin Invest. 2004; 114: 1098-1106Crossref PubMed Scopus (481) Google Scholar a class of compounds that undergo intracellular metabolism in an oxygen-dependent manner.22Evans S.M. Hahn S. Pook D.R. et al.Detection of hypoxia in human squamous cell carcinoma by EF5 binding.Cancer Res. 2000; 60: 2018-2024PubMed Google Scholar Tissue staining with these dyes revealed intriguing features of the mucosal oxygenation profile. First, basal hypoxia is detectable in normal, noninflamed intestinal epithelial cells, particularly in the colon epithelium. Therefore, low oxygen tension might regulate basal gene expression in these cells (ie, physiologic hypoxia). Second, inflammatory mucosal lesions observed in colitic mice were highly hypoxic or even anoxic, similar to those observed in large tumors. Several clinical studies have further defined the occurrence of hypoxia in IBD.23Giatromanolaki A. Sivridis E. Maltezos E. et al.Hypoxia inducible factor 1α and 2α overexpression in inflammatory bowel disease.J Clin Pathol. 2003; 56: 209-213Crossref PubMed Scopus (158) Google Scholar, 24Mariani F. Sena P. Marzona L. et al.Cyclooxygenase-2 and hypoxia-inducible factor-1α protein expression is related to inflammation, and up-regulated since the early steps of colorectal carcinogenesis.Cancer Lett. 2009; 279: 221-229Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 25Matthijsen R.A. Derikx J.P. Kuipers D. et al.Enterocyte shedding and epithelial lining repair following ischemia of the human small intestine attenuate inflammation.PLoS One. 2009; 4: e7045Crossref PubMed Scopus (45) Google Scholar Although mechanisms for local energy and oxygen depletion in the microenvironment of active inflammatory lesions have been partially elucidated, there is a growing body of data to indicate that microvascular deficits in IBD might contribute to mucosal hypoxia, through reduced intestinal blood supply and oxygen delivery; these are discussed further below. Notably, analyses of inflamed colon samples from IBD patients revealed prominent immunohistochemical staining for the hypoxia-inducible factors (HIFs) HIF-1 and HIF-223—transcription regulators of genes that control cell survival and functionality under hypoxic conditions. Some staining differences were noted between HIF-1 and HIF-2 in samples from patients with CD or ulcerative colitis (UC). For example, although HIF-1 was expressed focally within various stromal cells, HIF-2 appeared to be expressed more diffusely in CD samples. These studies also found that vascular density was significantly higher in samples from patients with CD or UC, compared with normal tissues, and that increased vascular density correlated with the expression of VEGF, a gene that is regulated by HIF.26Forsythe J.A. Jiang B.H. Iyer N.V. et al.Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.Mol Cell Biol. 1996; 16: 4604-4613Crossref PubMed Scopus (3177) Google Scholar, 27Pugh C.W. Ratcliffe P.J. Regulation of angiogenesis by hypoxia: role of the HIF system.Nat Med. 2003; 9: 677-684Crossref PubMed Scopus (1978) Google Scholar HIF is a member of the Per-ARNT-Sim family of basic helix-loop-helix transcription factors that binds hypoxia response elements (HREs) at target gene loci under hypoxic conditions.28Ratcliffe P.J. HIF-1 and HIF-2: working alone or together in hypoxia?.J Clin Invest. 2007; 117: 862-865Crossref PubMed Scopus (206) Google Scholar Functional HIF is a heterodimer that comprises a constitutive subunit (HIF-1β) and a hypoxia-inducible “α” component; stabilization of this α-subunit is regulated, in part, by a family of oxygen- and iron-dependent prolyl hydroxylase (PHD) enzymes.29Schofield C.J. Ratcliffe P.J. Oxygen sensing by HIF hydroxylases.Nat Rev Mol Cell Biol. 2004; 5: 343-354Crossref PubMed Scopus (1595) Google Scholar Three subunits have been identified (HIF-1α, HIF-2α, and HIF-3α), with the highest level of sequence homology conserved between HIF-1α and HIF-2α.30Wenger R.H. Stiehl D.P. Camenisch G. Integration of oxygen signaling at the consensus HRE.Sci STKE. 2005; 2005: re12PubMed Google Scholar Analyses of genetic mouse models indicate that HIF-1 and HIF-2 have nonredundant functions,28Ratcliffe P.J. HIF-1 and HIF-2: working alone or together in hypoxia?.J Clin Invest. 2007; 117: 862-865Crossref PubMed Scopus (206) Google Scholar despite their concurrent expression in many cell types, including intestinal epithelial cells.31Mastrogiannaki M. Matak P. Keith B. et al.HIF-2α, but not HIF-1α, promotes iron absorption in mice.J Clin Invest. 2009; 119: 1159-1166Crossref PubMed Scopus (356) Google Scholar Several studies have indicated that these proteins modulate the transcription of an overlapping but distinct set of genes (Table 1) and that transcriptional responses might be integrated in ways that support specific adaptations to hypoxia. For instance, transcriptional regulation of genes that encode glycolytic enzymes appears to be more specifically mediated by HIF-1 than HIF-2,32Hu C.J. Wang L.Y. Chodosh L.A. et al.Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation.Mol Cell Biol. 2003; 23: 9361-9374Crossref PubMed Scopus (1044) Google Scholar whereas HIF-2 selectively regulates gene expression of factors involved in duodenal iron homeostasis31Mastrogiannaki M. Matak P. Keith B. et al.HIF-2α, but not HIF-1α, promotes iron absorption in mice.J Clin Invest. 2009; 119: 1159-1166Crossref PubMed Scopus (356) Google Scholar and in early erythropoiesis. The N-terminal transactivation domain of HIF proteins has been proposed to mediate specificity for target genes via interactions with auxiliary transcription factors,28Ratcliffe P.J. HIF-1 and HIF-2: working alone or together in hypoxia?.J Clin Invest. 2007; 117: 862-865Crossref PubMed Scopus (206) Google Scholar but compelling evidence for this aspect remains elusive.Table 1Influence of HIF Signaling on Intestinal Mucosal Functions Implicated in IBD PathogenesisCompartmentFunctionIsoform specificityReferenceEpithelialBarrierHIF-1Furuta et al,5Furuta G.T. Turner J.R. Taylor C.T. et al.Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.J Exp Med. 2001; 193: 1027-1034Crossref PubMed Scopus (331) Google Scholar 2001Louis et al,36Louis N.A. Hamilton K.E. Canny G. et al.Selective induction of mucin-3 by hypoxia in intestinal epithelia.J Cell Biochem. 2006; 99: 1616-1627Crossref PubMed Scopus (109) Google Scholar 2006Karhausen et al,21Karhausen J. Furuta G.T. Tomaszewski J.E. et al.Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis.J Clin Invest. 2004; 114: 1098-1106Crossref PubMed Scopus (481) Google Scholar 2004Nucleotide metabolismHIF-1Synnestvedt et al,32Hu C.J. Wang L.Y. Chodosh L.A. et al.Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation.Mol Cell Biol. 2003; 23: 9361-9374Crossref PubMed Scopus (1044) Google Scholar 2002Iron transportHIF-2Mastrogiannaki et al,31Mastrogiannaki M. Matak P. Keith B. et al.HIF-2α, but not HIF-1α, promotes iron absorption in mice.J Clin Invest. 2009; 119: 1159-1166Crossref PubMed Scopus (356) Google Scholar 2009Cytokines/chemokinesHIF-1Shah et al,44Shah Y.M. Ito S. Morimura K. et al.Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade.Gastroenterology. 2008; 134 (e1–3): 2036-2048Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar 2008Migration/wound healingHIF-1Keely et al,41Keely S. Glover L.E. MacManus C.F. et al.Selective induction of integrin β1 by hypoxia-inducible factor: implications for wound healing.FASEB J. 2009; 23: 1338-1346Crossref PubMed Scopus (74) Google Scholar 2009Robinson et al,71Robinson A. Keely S. Karhausen J. et al.Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition.Gastroenterology. 2008; 134: 145-155Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar 2008Apoptosis/barrierHIF-1Cummins et al,70Cummins E.P. Seeballuck F. Keely S.J. et al.The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis.Gastroenterology. 2008; 134: 156-165Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar 2008EndothelialBarrierHIF-1Kong et al,40Kong T. Westerman K.A. Faigle M. et al.HIF-dependent induction of adenosine A2B receptor in hypoxia.FASEB J. 2006; 20: 2242-2250Crossref PubMed Scopus (279) Google Scholar 2006Nucleotide metabolismHIF-1Kong et al,40Kong T. Westerman K.A. Faigle M. et al.HIF-dependent induction of adenosine A2B receptor in hypoxia.FASEB J. 2006; 20: 2242-2250Crossref PubMed Scopus (279) Google Scholar 2006Eltzschig et al,34Eltzschig H.K. Ibla J.C. Furuta G.T. et al.Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors.J Exp Med. 2003; 198: 783-796Crossref PubMed Scopus (397) Google Scholar 2003AngiogenesisHIF-1/HIF-2Pugh et al,27Pugh C.W. Ratcliffe P.J. Regulation of angiogenesis by hypoxia: role of the HIF system.Nat Med. 2003; 9: 677-684Crossref PubMed Scopus (1978) Google Scholar 2003MyeloidBacterial killingHIF-1Peyssonnaux et al,46Peyssonnaux C. Datta V. Cramer T. et al.HIF-1α expression regulates the bactericidal capacity of phagocytes.J Clin Invest. 2005; 115: 1806-1815Crossref PubMed Scopus (533) Google Scholar 2005ATP generationHIF-1Cramer et al,43Cramer T. Yamanishi Y. Clausen B.E. et al.HIF-1α is essential for myeloid cell-mediated inflammation.Cell. 2003; 112: 645-657Abstract Full Text Full Text PDF PubMed Scopus (1582) Google Scholar 2003Cytokine productionHIF-1/HIF-2Acosta–Iborra et al,51Acosta-Iborra B. Elorza A. Olazabal I.M. et al.Macrophage oxygen sensing modulates antigen presentation and phagocytic functions involving IFN-γ production through the HIF-1 α transcription factor.J Immunol. 2009; 182: 3155-3164Crossref PubMed Scopus (72) Google Scholar 2009Colitis-associated tumor infiltrationHIF-2Imtiyaz et al,79Imtiyaz H.Z. Williams E.P. Hickey M.M. et al.Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation.J Clin Invest. 2010; 120: 2699-2714Crossref PubMed Scopus (339) Google Scholar 2010T-cellTCR signalingHIF-1Neumann et al,49Neumann A.K. Yang J. Biju M.P. et al.Hypoxia inducible factor 1 α regulates T-cell receptor signal transduction.Proc Natl Acad Sci U S A. 2005; 102: 17071-17076Crossref PubMed Scopus (91) Google Scholar 2005HepaticErythropoietin productionHIF-2Rankin et al,80Rankin E.B. Biju M.P. Liu Q. et al.Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo.J Clin Invest. 2007; 117: 1068-1077Crossref PubMed Scopus (435) Google Scholar 2007GeneralGlucose metabolismHIF-1Hu et al,32Hu C.J. Wang L.Y. Chodosh L.A. et al.Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation.Mol Cell Biol. 2003; 23: 9361-9374Crossref PubMed Scopus (1044) Google Scholar 2003GlycolysisHIF-1Vermeulen et al,81Vermeulen N. Vermeire S. Arijs I. et al.Seroreactivity against glycolytic enzymes in inflammatory bowel disease.Inflamm Bowel Dis. 2011; 17: 557-564Crossref PubMed Scopus (16) Google Scholar 2011TCR, T-cell receptor. Open table in a new tab TCR, T-cell receptor. During mucosal inflammation, HIF has a protective role5Furuta G.T. Turner J.R. Taylor C.T. et al.Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.J Exp Med. 2001; 193: 1027-1034Crossref PubMed Scopus (331) Google Scholar, 33Comerford K.M. Wallace T.J. Karhausen J. et al.Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene.Cancer Res. 2002; 62: 3387-3394PubMed Google Scholar, 34Eltzschig H.K. Ibla J.C. Furuta G.T. et al.Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors.J Exp Med. 2003; 198: 783-796Crossref PubMed Scopus (397) Google Scholar, 35Synnestvedt K. Furuta G.T. Comerford K.M. et al.Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia.J Clin Invest. 2002; 110: 993-1002Crossref PubMed Scopus (590) Google Scholar; microarray analyses of differentially expressed messenger RNA in cultured epithelial cells subjected to hypoxia and animal models of inflammation showed that the HIF-regulated transcriptional profile promotes intestinal epithelial barrier function. Further investigation of mechanisms related to hypoxia-elicted barrier protection revealed interesting features. First, expression of the functional proteins encoded by these transcripts was localized to the most luminal apical aspect of polarized epithelia.5Furuta G.T. Turner J.R. Taylor C.T. et al.Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.J Exp Med. 2001; 193: 1027-1034Crossref PubMed Scopus (331) Google Scholar, 33Comerford K.M. Wallace T.J. Karhausen J. et al.Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene.Cancer Res. 2002; 62: 3387-3394PubMed Google Scholar, 35Synnestvedt K. Furuta G.T. Comerford K.M. et al.Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia.J Clin Invest. 2002; 110: 993-1002Crossref PubMed Scopus (590) Google Scholar Second, molecular dissection of the hypoxia-elicited pathway(s) for this apical gene cluster revealed a high propensity for regulation by HIF. Third, HIF-dependent, epithelial barrier protective pathways induced by hypoxia tend to be more nonconventional regulators of barrier function than prototypical junction proteins such as occludin or claudin(s). Rather, HIF-regulated signaling promotes overall tissue integrity, influencing functions that range from increased mucin production36Louis N.A. Hamilton K.E. Canny G. et al.Selective induction of mucin-3 by hypoxia in intestinal epithelia.J Cell Biochem. 2006; 99: 1616-1627Crossref PubMed Scopus (109) Google Scholar by molecules that modify mucins, such as intestinal trefoil factor,5Furuta G.T. Turner J.R. Taylor C.T. et al.Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.J Exp Med. 2001; 193: 1027-1034Crossref PubMed Scopus (331) Google Scholar to xenobiotic clearance by P-glycoprotein,33Comerford K.M. Wallace T.J. Karhausen J. et al.Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene.Cancer Res. 2002; 62: 3387-3394PubMed Google Scholar to nucleotide metabolism by 5′-ectonucleotidase (CD73)34Eltzschig H.K. Ibla J.C. Furuta G.T. et al.Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors.J Exp Med. 2003; 198: 783-796Crossref PubMed Scopus (397) Google Scholar, 35Synnestvedt K. Furuta G.T. Comerford K.M. et al.Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia.J Clin Invest. 2002; 110: 993-1002Crossref PubMed Scopus (590) Google Scholar, 37Louis N.A. Robinson A.M. MacManus C.F. et al.Control of IFN-αA by CD73: implications for mucosal inflammation.J Immunol. 2008; 180: 4246-4255PubMed Google Scholar, 38Thompson L.F. Eltzschig H.K. Ibla J.C. et al.Crucial role for ecto-5'-nucleotidase (CD73) in vascular leakage during hypoxia.J Exp Med. 2004; 200: 1395-1405Crossref PubMed Scopus (440) Google Scholar and nucleotide signaling through the adenosine A2B receptor.34Eltzschig H.K. Ibla J.C. Furuta G.T. et al.Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors.J Exp Med. 2003; 198: 783-796Crossref PubMed Scopus (397) Google Scholar, 39Frick J.S. MacManus C.F. Scully M. et al.Contribution of adenosine A2B receptors to inflammatory parameters of experimental colitis.J Immunol. 2009; 182: 4957-4964Crossref PubMed Scopus (123) Google Scholar, 40Kong T. Westerman K.A. Faigle M. et al.HIF-dependent induction of adenosine A2B receptor" @default.
• W2078703212 created "2016-06-24" @default.
• W2078703212 creator A5049650132 @default.
• W2078703212 creator A5051618208 @default.
• W2078703212 date "2011-05-01" @default.
• W2078703212 modified "2023-10-09" @default.
• W2078703212 title "Hypoxia and Metabolic Factors That Influence Inflammatory Bowel Disease Pathogenesis" @default.
• W2078703212 cites W1501589213 @default.
• W2078703212 cites W1513297739 @default.
• W2078703212 cites W1536433213 @default.
• W2078703212 cites W1651526390 @default.
• W2078703212 cites W1738785473 @default.
• W2078703212 cites W1757383019 @default.
• W2078703212 cites W1845306201 @default.
• W2078703212 cites W1888121068 @default.
• W2078703212 cites W1957500099 @default.
• W2078703212 cites W1970548725 @default.
• W2078703212 cites W1972760177 @default.
• W2078703212 cites W1972987064 @default.
• W2078703212 cites W1974600816 @default.
• W2078703212 cites W1974718508 @default.
• W2078703212 cites W1976041167 @default.
• W2078703212 cites W1976555781 @default.
• W2078703212 cites W1988377666 @default.
• W2078703212 cites W1989538067 @default.
• W2078703212 cites W1991346678 @default.
• W2078703212 cites W1995915603 @default.
• W2078703212 cites W2005539293 @default.
• W2078703212 cites W2007522021 @default.
• W2078703212 cites W2008009624 @default.
• W2078703212 cites W2010356452 @default.
• W2078703212 cites W2010542363 @default.
• W2078703212 cites W2011843272 @default.
• W2078703212 cites W2013818100 @default.
• W2078703212 cites W2018782206 @default.
• W2078703212 cites W2029696541 @default.
• W2078703212 cites W2031565553 @default.
• W2078703212 cites W2041418689 @default.
• W2078703212 cites W2041607290 @default.
• W2078703212 cites W2044192395 @default.
• W2078703212 cites W2049346572 @default.
• W2078703212 cites W2054149870 @default.
• W2078703212 cites W2066077682 @default.
• W2078703212 cites W2071062200 @default.
• W2078703212 cites W2072138444 @default.
• W2078703212 cites W2072862372 @default.
• W2078703212 cites W2073759680 @default.
• W2078703212 cites W2077198680 @default.
• W2078703212 cites W2082083390 @default.
• W2078703212 cites W2085100595 @default.
• W2078703212 cites W2089141914 @default.
• W2078703212 cites W2089916504 @default.
• W2078703212 cites W2091068407 @default.
• W2078703212 cites W2096468570 @default.
• W2078703212 cites W2098921416 @default.
• W2078703212 cites W2101084498 @default.
• W2078703212 cites W2102619095 @default.
• W2078703212 cites W2103326429 @default.
• W2078703212 cites W2105747004 @default.
• W2078703212 cites W2108623724 @default.
• W2078703212 cites W2108780695 @default.
• W2078703212 cites W2111850449 @default.
• W2078703212 cites W2123891308 @default.
• W2078703212 cites W2126496496 @default.
• W2078703212 cites W2126904401 @default.
• W2078703212 cites W2133938746 @default.
• W2078703212 cites W2135824704 @default.
• W2078703212 cites W2138216041 @default.
• W2078703212 cites W2139759128 @default.
• W2078703212 cites W2139766266 @default.
• W2078703212 cites W2142622000 @default.
• W2078703212 cites W2144625075 @default.
• W2078703212 cites W2145189896 @default.
• W2078703212 cites W2147160899 @default.
• W2078703212 cites W2149472502 @default.
• W2078703212 cites W2149779130 @default.
• W2078703212 cites W2151593963 @default.
• W2078703212 cites W2155292937 @default.
• W2078703212 cites W2163069245 @default.
• W2078703212 cites W2163788153 @default.
• W2078703212 cites W2166798770 @default.
• W2078703212 cites W2167786713 @default.
• W2078703212 cites W4234288885 @default.
• W2078703212 cites W4250417345 @default.
• W2078703212 doi "https://doi.org/10.1053/j.gastro.2011.01.056" @default.
• W2078703212 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3093411" @default.
• W2078703212 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21530741" @default.
• W2078703212 hasPublicationYear "2011" @default.
• W2078703212 type Work @default.
• W2078703212 sameAs 2078703212 @default.
• W2078703212 citedByCount "97" @default.
• W2078703212 countsByYear W20787032122012 @default.
• W2078703212 countsByYear W20787032122013 @default.
• W2078703212 countsByYear W20787032122014 @default.
• W2078703212 countsByYear W20787032122015 @default.
• W2078703212 countsByYear W20787032122016 @default.
• W2078703212 countsByYear W20787032122017 @default.
• W2078703212 countsByYear W20787032122018 @default.

• next