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Review

Metabolic regulation of intestinal epithelial barrier during inflammation

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Article: e970936 | Received 29 Jul 2014, Accepted 25 Sep 2014, Published online: 25 Feb 2015

References

  • Kominsky DJ, Campbell EL, Colgan SP. Metabolic shifts in immunity and inflammation. J Immunol 2010;184:4062-8; PMID:20368286; http://dx.doi.org/10.4049/jimmunol.0903002
  • Colgan SP, Taylor CT. Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 2010;7:281-287; PMID:20368740; http://dx.doi.org/10.1038/nrgastro.2010.39
  • Lewis JS, Lee JA, Underwood JC, Harris AL, Lewis CE. Macrophage responses to hypoxia: relevance to disease mechanisms. J Leukoc Biol 1999;66:889-900; PMID:10614769
  • Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 2005;5:844-52; PMID:16239903; http://dx.doi.org/10.1038/nri1710
  • Sitkovsky M, Lukashev D. Regulation of immune cells by local-tissue oxygen tension: HIF1 a and adenosine receptors. Nat Rev Immunol 2005;5:712-21; PMID:16110315; http://dx.doi.org/10.1038/nri1685
  • Shepherd AP. Metabolic control of intestinal oxygenation and blood flow. Fed Proc 1982;41:2084-9; PMID:7075783
  • Furuta GT, Turner JR, Taylor CT, Hershberg RM, Comerford K, Narravula S, et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J Exp Med 2001;193:1027-34; PMID:11342587; http://dx.doi.org/10.1084/jem.193.9.1027
  • Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor. Ann Intern Med 1986;105:883-5; PMID:3777713; http://dx.doi.org/10.7326/0003-4819-105-6-883
  • Laukoetter MG, Nava P, Nusrat A. Role of the intestinal barrier in inflammatory bowel disease. World J Gastroenterol 2008;14:401-7; PMID:18200662; http://dx.doi.org/10.3748/wjg.14.401
  • Taylor CT, Colgan SP. Hypoxia and gastrointestinal disease. J Mol Med 2007;85:1295-300; PMID:18026919; http://dx.doi.org/10.1007/s00109-007-0277-z
  • Clavel 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;8:25-43; PMID:17542334
  • Kagnoff MF, Eckmann L. Epithelial cells as sensors for microbial infection. J Clin Invest 1997;100:6-10; PMID:9202050; http://dx.doi.org/10.1172/JCI119522
  • Madsen K, Cornish A, Soper P, McKaigney C, Jijon H, Yachimec C, et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 2001;121:580-91; PMID:11522742; http://dx.doi.org/10.1053/gast.2001.27224
  • Furuta GT, Turner JR, Taylor CT, Hershberg RM, Comerford KM, Narravula S, et al. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Ex. Med. 2001;193:1027-1034; PMID:11342587
  • Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 2002;62:3387-94; PMID:12067980
  • Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, et al. Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 (HIF-1) mediates permeability changes in intestinal epithelia. J. Clin. Invest. 2002;110:993-1002; PMID:12370277; http://dx.doi.org/10.1172/JCI0215337
  • Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA, Enjyoji K, et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Ex. Med. 2003;198:783-796; PMID:12939345
  • Semenza GL. Regulation of Metabolism by Hypoxia-Inducible Factor 1. Cold Spring Harb Symp Quant Biol 2011;76:347-53; PMID:21785006
  • Semenza GL. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 2001;107:1-3; PMID:11595178; http://dx.doi.org/10.1016/S0092-8674(01)00518-9
  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271-5; PMID:10353251; http://dx.doi.org/10.1038/20459
  • Tanimoto K, Makino Y, Pereira T, Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1 a by the von Hippel-Lindau tumor suppressor protein. Embo J 2000;19:4298-309; PMID:10944113; http://dx.doi.org/10.1093/emboj/19.16.4298
  • Lando D, Peet DJ, Whelan DA, Gorman JJ, Murray LW. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Sci 2002;295:858-861; PMID:11823643; http://dx.doi.org/10.1126/science.1068592
  • Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ, Fallon PG, Taylor CT. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 2008;134:156-65; PMID:18166353; http://dx.doi.org/10.1053/j.gastro.2007.10.012
  • Han IO, Kim HS, Kim HC, Joe EH, Kim WK. Synergistic expression of inducible nitric oxide synthase by phorbol ester and interferon-gamma is mediated through NF-kappaB and ERK in microglial cells. J Neurosci Res 2003;73:659-69; PMID:12929133; http://dx.doi.org/10.1002/jnr.10706
  • Karhausen JO, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 2004;114:1098-1106; PMID:15489957; http://dx.doi.org/10.1172/JCI200421086
  • Morote-Garcia JC, Rosenberger P, Nivillac NM, Coe IR, Eltzschig HK. Hypoxia-inducible factor-dependent repression of equilibrative nucleoside transporter 2 attenuates mucosal inflammation during intestinal hypoxia. Gastroenterology 2009;136:607-18; PMID:19105964; http://dx.doi.org/10.1053/j.gastro.2008.10.037
  • Robinson A, Keely S, Karhausen J, Gerich ME, Furuta GT, Colgan SP. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 2008;134:145-55; PMID:18166352; http://dx.doi.org/10.1053/j.gastro.2007.09.033
  • Shah YM, Ito S, Morimura K, Chen C, Yim SH, Haase VH, Gonzalez FJ. Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 2008;134:2036-48, 2048 e1-3; PMID:18439915; http://dx.doi.org/10.1053/j.gastro.2008.03.009
  • Giatromanolaki A, Sivridis E, Maltezos E, Papazoglou D, Simopoulos C, Gatter KC, Harris AL, Koukourakis MI. Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol 2003;56:209-13; PMID:12610101; http://dx.doi.org/10.1136/jcp.56.3.209
  • Mariani F, Sena P, Marzona L, Riccio M, Fano R, Manni P, Gregorio CD, Pezzi A, Leon MP, Monni S, et al. Cyclooxygenase-2 and Hypoxia-Inducible Factor-1alpha protein expression is related to inflammation, and up-regulated since the early steps of colorectal carcinogenesis. Cancer Lett 2009;279:221-9; PMID:19268443; http://dx.doi.org/10.1016/j.canlet.2009.02.001
  • Matthijsen RA, Derikx JP, Kuipers D, van Dam RM, Dejong CH, Buurman WA. Enterocyte shedding and epithelial lining repair following ischemia of the human small intestine attenuate inflammation. PLoS One 2009;4:e7045; PMID:19753114
  • Louis NA, Hamilton KE, Canny G, Shekels LL, Ho SB, Colgan SP. Selective induction of mucin-3 by hypoxia in intestinal epithelia. J Cell Biochem 2006;99:1616-27; PMID:16823775; http://dx.doi.org/10.1002/jcb.20947
  • Glover LE, Bowers BE, Saeedi B, Ehrentraut SF, Campbell EL, Bayless AJ, Dobrinskikh E, Kendrick AA, Kelly CJ, Burgess A et al. Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. Proc Natl Acad Sci U S A. 2013;110:19820-5; PMID:24248342; http://dx.doi.org/10.1073/pnas.1302840110
  • Colgan SP, Eltzschig HK. Adenosine and hypoxia-inducible factor signaling in intestinal injury and recovery. Annu Rev Physiol. 2012;74:153-75; PMID:21942704; http://dx.doi.org/10.1146/annurev-physiol-020911-153230
  • Weissmuller T, Campbell EL, Rosenberger P, Scully M, Beck PL, Furuta GT,Colgan SP. PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell-expressed ecto-NTPDases. J Clin Invest 2008;118:3682-92; PMID:18924612; http://dx.doi.org/10.1172/JCI35874
  • Zimmermann H, Braun N. Ecto-nucleotidases–molecular structures, catalytic properties, and functional roles in the nervous system. Prog Brain Res 1999;120:371-85; PMID:10551012; http://dx.doi.org/10.1016/S0079-6123(08)63570-0
  • Linden J. Molecular approach to adenosine receptors: receptor-mediated mechanisms of tissue protection. Annu Rev Pharmacol Toxicol 2001;41:775-87; PMID:11264476; http://dx.doi.org/10.1146/annurev.pharmtox.41.1.775
  • Chin AC, Parkos CA. Pathobiology of neutrophil transepithelial migration: implications in mediating epithelial injury. Annu Rev Pathol 2007;2:111-43; PMID:18039095; http://dx.doi.org/10.1146/annurev.pathol.2.010506.091944
  • Lennon PF, Taylor CT, Stahl GL, Colgan SP. Neutrophil-derived 5'-adenosine monophosphate promotes endothelial barrier function via CD73-mediated conversion to adenosine and endothelial A2B receptor activation. J Exp Med 1998;188:1433-43; PMID:9782120; http://dx.doi.org/10.1084/jem.188.8.1433
  • Dejana E, Spagnuolo R, Bazzoni G. Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration. Thromb Haemost 2001;86:308-15; PMID:11487019
  • Ley K. Plugging the leaks. Nat Med 2001;7:1105-6; PMID:11590428; http://dx.doi.org/10.1038/nm1001-1105
  • Comerford KM, Lawrence DW, Synnestvedt K, Levi BP, Colgan SP. Role of vasodilator-stimulated phosphoprotein in PKA-induced changes in endothelial junctional permeability. Faseb J 2002;16:583-5; PMID:11919161
  • Eltzschig HK, Thompson LF, Karhausen J, Cotta RJ, Ibla JC, Robson SC, Colgan SP. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: Coordination by extracellular nucleotide metabolism. Blood 2004;104:3986-3992; PMID:15319286; http://dx.doi.org/10.1182/blood-2004-06-2066
  • Novak I. ATP as a signaling molecule: the exocrine focus. News Physiol Sci 2003;18:12-7; PMID:12531926
  • Thompson LF, Eltzschig HK, Ibla JC, Van De Wiele CJ, Resta R, Morote-Garcia JC, Colgan SP. Crucial role for ecto-5'-nucleotidase (CD73) in vascular leak during hypoxia. J. Exp. Med. 2004;200:1395-1405; PMID:15583013
  • McDonald DM, Thurston G, Baluk P. Endothelial gaps as sites for plasma leakage in inflammation. Microcirculation 1999;6:7-22; PMID:10100186; http://dx.doi.org/10.1111/j.1549-8719.1999.tb00084.x
  • Takano T, Clish CB, Gronert K, Petasis N, Serhan CN. Neutrophil-mediated changes in vascular permeability are inhibited by topical application of aspirin-triggered 15-epi-lipoxin A4 and novel lipoxin B4 stable analogues. J Clin Invest 1998;101:819-26; PMID:9466977; http://dx.doi.org/10.1172/JCI1578
  • Eltzschig HK, Rivera-Nieves J, Colgan SP. Targeting the A2B adenosine receptor during gastrointestinal ischemia and inflammation. Expert Opin Ther Targets 2009;13:1267-77; PMID:19769545; http://dx.doi.org/10.1517/14728220903241666
  • Weissmueller T, Eltzschig HK, Colgan SP. Dynamic purine signalling and metabolism during neutrophil-endothelial interactions. Purinergic Signalling 2005;1:229-239; PMID:18404508; http://dx.doi.org/10.1007/s11302-005-6323-9
  • Ivanov AI, Parkos CA, Nusrat A. Cytoskeletal regulation of epithelial barrier function during inflammation. Am J Pathol 2010;177:512-24. Epub 2010 Jun 25; PMID:20581053; http://dx.doi.org/10.2353/ajpath.2010.100168
  • Tsukamoto T, Nigam SK. Role of tyrosine phosphorylation in the reassembly of occludin and other tight junction proteins. Am. J. Physiol. Renal Physiol. 1999;276:F737-F750; PMID:10330056;
  • Taylor CT, Dzus AL, Colgan SP. Autocrine regulation of intestinal epithelial permeability induced by hypoxia: Role for basolateral release of tumor necrosis factor-a (TNF-a). Gastroenterol. 1998;114:657-668; http://dx.doi.org/10.1016/S0016-5085(98)70579-7
  • Friedman GB, Taylor CT, Parkos CA, Colgan SP. Epithelial permeability induced by neutrophil transmigration is potentiated by hypoxia: role of intracellular cAMP. J. Cell. Physiol. 1998;176:76-84; PMID:9618147
  • Tsukamoto T, Nigam SK. Tight junction proteins form large complexes and associate with the cytoskeleton in an ATP depletion model for reversible junction assembly. J. Biol. Chem. 1997;272:16133-16139; PMID:9195909
  • Kevil CG, Oshima T, Alexander B, Coe LL, Alexander JS. H(2)O(2)-mediated permeability: role of MAPK and occludin. Am J Physiol Cell Physiol 2000;279:C21-30; PMID:10898713
  • Wu HM, Huang QB, Yuan Y, Granger HJ. VEGF induces NO-dependent hyperpermeability in coronary venules. Am. J. Physiol. Heart Circ. Physiol. 1996;271:H2735-2739; PMID:8997338
  • Molitoris BA, Leiser J, Wagner MC. Role of the actin cytoskeleton in ischemia-induced cell injury and repair. Pediatr. Nephrol. 1997;11:761-767; PMID:9438662
  • Bacallao RA, Garginkel A, Monke S, Zampighi G, Mandel LJ. ATP depletion: a novel method to study junctional properties in epithelial tissues. I. Rearrangement of the actin cytoskeleton. J. Cell. Sci. 1994;107:3301-3313; PMID:7706387
  • Molitoris BA, Dahl R, Hosford M. Cellular ATP depletion induces disruption of the spectrin cytoskeletal network. Am. J. Physiol. 1996;271:f790-798; PMID:8898008
  • Zharikov SI, Block ER. Association of L-arginine transporters with fodrin: implications for hypoxic ihibition of arginine uptake. Am. J. Physiol. 2000;278:L111-117; PMID:10645898
  • Hochachka PW, Buck LT, Doll CJ, Land SC. Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Natl Acad Sci U S A 1996;93:9493-8; PMID:8790358; http://dx.doi.org/10.1073/pnas.93.18.9493
  • Shapiro M, Matthews J, Hecht G, Delp C, Madara JL. Stablization of F-actin prevents cAMP-elicited Cl- secretion in T84 cells. J. Clin. Invest. 1991;87:1903-9; PMID:1645745; http://dx.doi.org/10.1172/JCI115215
  • Dye JF, Leach L, Clark P, Firth JA. Cyclic AMP and acidic fibroblast growth factor have opposing efffects on tight and adherens junctions in microvascular endothelial cells in vitro. Microvasc. Res. 2001;62:94-113; PMID:11516239
  • Adamson RH, Liu B, Fry GN, Rubin LL, Curry FE. Microvascular permeability and number of tight junctions are modulated by cAMP. Am J Physiol 1998;274:H1885-94; PMID:9841516
  • Stelzner TJ, Weil JV, O'Brien RF. Role of cyclic adenosine monophosphate in the induction of endothelial barrier properties. J. Cell. Physiol. 1989;139:157-166; PMID:2540209
  • Lawrence DW, Comerford KM, Colgan SP. Role of VASP in reestablishment of epithelial tight junction assembly after Ca2+ switch. Am J Physiol Cell Physiol 2002;282:C1235-45; PMID:11997237; http://dx.doi.org/10.1152/ajpcell.00288.2001
  • Dejana E. Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis. J. Clin. Invest. 1996;98:1949-1953; PMID:8903311; http://dx.doi.org/10.1172/JCI118997
  • Cuzzocrea S, Mazzon E, De Sarro A, Caputi AP. Role of free radicals and poly(ADP-ribose) synthetase in intestinal tight junction permeability. Mol Med 2000;6:766-78; PMID:11071271
  • Meyer TN, Schwesinger C, Ye J, Denker BM, Nigam SK. Reassembly of the tight junction after oxidative stress depends on tyrosine kinase activity. J Biol Chem 2001;276:22048-55; PMID:11294856; http://dx.doi.org/10.1074/jbc.M011477200
  • Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, et al. Hypoxia-inducible factor-1 a-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A. 2012;109:E2784-93; PMID:22988108; http://dx.doi.org/10.1073/pnas.1202366109
  • Glover LE, Irizarry K, Scully M, Campbell EL, Bowers BE, Aherne CM, Kominsky DJ, MacManus CF, Colgan SP. IFN-gamma attenuates HIF activity in intestinal epithelial cells through transcriptional repression of HIF-1beta. J Immunol 2011;186:1790-8; PMID:21199896; http://dx.doi.org/10.4049/jimmunol.1001442
  • Hirota SA, Fines K, Ng J, Traboulsi D, Lee J, Ihara E, et al. Hypoxia-inducible factor signaling provides protection in Clostridium difficile-induced intestinal injury. Gastroenterology 2010;139:259-69 e3; PMID:20347817; http://dx.doi.org/10.1053/j.gastro.2010.03.045
  • Hindryckx P, De Vos M, Jacques P, Ferdinande L, Peeters H, Olievier K, Bogaert S, Brinkman B, Vandenabeele P, Elewaut D et al. Hydroxylase inhibition abrogates TNF-a-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD. J Immunol. 2010;185:6306-16; PMID:20943999; http://dx.doi.org/10.4049/jimmunol.1002541
  • Keely S, Glover LE, Weissmueller T, MacManus CF, Fillon S, Fennimore B, Colgan SP. Hypoxia-inducible factor-dependent regulation of platelet-activating factor receptor as a route for gram-positive bacterial translocation across epithelia. Mol Biol Cell 2009;21:538-46; PMID:20032301; http://dx.doi.org/10.1091/mbc.E09-07-0573
  • Louis NA, Hamilton KE, Kong T, Colgan SP. HIF-dependent induction of apical CD55 coordinates epithelial clearance of neutrophils. Faseb J 2005;19:950-959; PMID:15923405; http://dx.doi.org/10.1096/fj.04-3251com
  • Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 2004;114:1098-106; PMID:15489957; http://dx.doi.org/10.1172/JCI200421086
  • Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev. 2000;80:1107-213; PMID:10893433
  • Ivanov AI, Parkos CA, Nusrat A. Cytoskeletal regulation of epithelial barrier function during inflammation. Am J Pathol. 2010;177:512-24; PMID:20581053; http://dx.doi.org/10.2353/ajpath.2010.100168
  • Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009;9:799-809; PMID:19855405; http://dx.doi.org/10.1038/nri2653
  • Song JC, Hrnjez BJ, Farokhzad OC, Matthews JB. PKC-epsilon regulates basolateral endocytosis in human T84 intestinal epithelia: role of F-actin and MARCKS. Am J Physiol. 1999;277:C1239-49; PMID:10600776
  • Culic O, Gruwel ML, Schrader J. Energy turnover of vascular endothelial cells. Am J Physiol. 1997;273:C205-13; PMID:9252458
  • Daniel JL, Molish IR, Robkin L, Holmsen H. Nucleotide exchange between cytosolic ATP and F-actin-bound ADP may be a major energy-utilizing process in unstimulated platelets. Eur J Biochem. 1986;156:677-84; PMID:3699030; http://dx.doi.org/10.1111/j.1432-1033.1986.tb09631.x
  • Kaelin WG, Jr., Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 2008;30:393-402; PMID:18498744; http://dx.doi.org/10.1016/j.molcel.2008.04.009
  • Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J, et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-b, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A 2006;103:18154-9; PMID:17114296; http://dx.doi.org/10.1073/pnas.0602235103
  • Aragones J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 2008;40:170-80; PMID:18176562; http://dx.doi.org/10.1038/ng.2007.62
  • Schneider M, Van Geyte K, Fraisl P, Kiss J, Aragones J, Mazzone M, et al. Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury. Gastroenterology 2009; PMID:19818783
  • Tambuwala MM, Cummins EP, Lenihan CR, Kiss J, Stauch M, Scholz CC, Fraisl P, Lasitschka F, Mollenhauer M, Saunders SP et al. Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function. Gastroenterology 2010; 139:2093-101; PMID:20600011
  • Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 2009;136:839-51; PMID:19217150; http://dx.doi.org/10.1016/j.cell.2009.01.020
  • Ozolins TR, Fisher TS, Nadeau DM, Stock JL, Klein AS, Milici AJ, Morton D, Wilhelms MB, Brissette WH, Li B. Defects in embryonic development of EGLN1/PHD2 knockdown transgenic mice are associated with induction of Igfbp in the placenta. Biochem Biophys Res Commun 2009;390:372-6; PMID:19683511;http://dx.doi.org/10.1016/j.bbrc.2009.08.057
  • Bishop T, Gallagher D, Pascual A, Lygate CA, de Bono JP, Nicholls LG, Ortega-Saenz P, Oster H, Wijeyekoon B, Sutherland AI, et al. Abnormal sympathoadrenal development and systemic hypotension in PHD3-/- mice. Mol Cell Biol 2008;28:3386-400; PMID:18332118; http://dx.doi.org/10.1128/MCB.02041-07
  • Mole DR, Schlemminger I, McNeill LA, Hewitson KS, Pugh CW, Ratcliffe PJ, Schofield CJ. Two-oxoglutarate analogue inhibitors of HIF prolyl hydroxylase. Bioorg Med Chem Lett 2003;13:2677-80; PMID:12873492; http://dx.doi.org/10.1016/S0960-894X(03)00539-0
  • Masson N, Ratcliffe PJ. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels. J Cell Sci 2003;116:3041-9; PMID:12829734; http://dx.doi.org/10.1242/jcs.00655
  • Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004;5:343-54; PMID:15122348; http://dx.doi.org/10.1038/nrm1366
  • Bruick RK. Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev 2003;17:2614-23; PMID:14597660; http://dx.doi.org/10.1101/gad.1145503
  • Nwogu JI, Geenen D, Bean M, Brenner MC, Huang X, Buttrick PM. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation 2001;104:2216-21; PMID:11684634; http://dx.doi.org/10.1161/hc4301.097193
  • Schlemminger I, Mole DR, McNeill LA, Dhanda A, Hewitson KS, Tian YM, Ratcliffe PJ, Pugh CW, Schofield CJ. Analogues of dealanylalahopcin are inhibitors of human HIF prolyl hydroxylases. Bioorg Med Chem Lett 2003;13:1451-4; PMID:12668010; http://dx.doi.org/10.1016/S0960-894X(03)00149-5
  • Keely S, Campbell EL, Baird AW, Hansbro PM, Shalwitz RA, Kotsakis A, McNamee EN, Eltzschig HK, Kominsky DJ, et al. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal Immunol 2013;22:114-123; PMID:23695513
  • Okumura CY, Hollands A, Tran DN, Olson J, Dahesh S, von Kockritz-Blickwede M, Thienphrapa W, Corle C, Jeung SN, Kotsakis A et al. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection. J Mol Med 2012;28:1079-1089; PMID:22371073; http://dx.doi.org/10.1007/s00109-012-0882-3

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