Skip to main content

Advertisement

Log in

Molecular oxygen sensing: implications for visceral surgery

  • Review Article
  • Published:
Langenbeck's Archives of Surgery Aims and scope Submit manuscript

Abstract

Background

Since mammalian cells rely on the availability of oxygen, they have devised mechanisms to sense environmental oxygen tension, and to efficiently counteract oxygen deprivation (hypoxia). These adaptive responses to hypoxia are essentially mediated by hypoxia inducible transcription factors (HIFs). Three HIF prolyl hydroxylase enzymes (PHD1, PHD2 and PHD3) function as oxygen sensing enzymes, which regulate the activity of HIFs in normoxic and hypoxic conditions. Many of the compensatory functions exerted by the PHD–HIF system are of immediate surgical relevance since they regulate the biological response of ischemic tissues following ligation of blood vessels, of oxygen-deprived inflamed tissues, and of tumors outgrowing their vascular supply.

Purpose

Here, we outline specific functions of PHD enzymes in surgically relevant pathological conditions, and discuss how these functions might be exploited in order to support the treatment of surgically relevant diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12(12):5447–5454

    PubMed  CAS  Google Scholar 

  2. Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294(5545):1337–1340

    Article  PubMed  CAS  Google Scholar 

  3. Epstein AC, Gleadle JM, McNeill LA et al (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107(1):43–54

    Article  PubMed  CAS  Google Scholar 

  4. Fandrey J, Gorr TA, Gassmann M (2006) Regulating cellular oxygen sensing by hydroxylation. Cardiovasc Res 71(4):642–651

    Article  PubMed  CAS  Google Scholar 

  5. Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9(6):677–684

    Article  PubMed  CAS  Google Scholar 

  6. Aragones J, Schneider M, Van Geyte K et al (2008) Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 40(2):170–180

    Article  PubMed  CAS  Google Scholar 

  7. Tambuwala MM, Cummins EP, Lenihan CR et al (2010) Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function. Gastroenterology 139(6):2093–2101

    Article  PubMed  CAS  Google Scholar 

  8. Schneider M, Van Geyte K, Fraisl P et al. (2010) Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury. Gastroenterology 138(3):1143–1154 e1141–1142.

    Google Scholar 

  9. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185

    Article  PubMed  Google Scholar 

  10. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3(3):187–197

    Article  PubMed  CAS  Google Scholar 

  11. Jeoung NH, Wu P, Joshi MA, Jaskiewicz J, Bock CB, Depaoli-Roach AA, Harris RA (2006) Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation. Biochem J 397(3):417–425

    Article  PubMed  CAS  Google Scholar 

  12. Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9(6):425–434

    Article  PubMed  CAS  Google Scholar 

  13. Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 281(14):9030–9037

    Article  PubMed  CAS  Google Scholar 

  14. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23(24):9361–9374

    Article  PubMed  CAS  Google Scholar 

  15. Moussavian MR, Scheuer C, Schmidt M et al (2011) Multidrug donor preconditioning prevents cold liver preservation and reperfusion injury. Langenbecks Arch Surg 396(2):231–241

    Article  PubMed  Google Scholar 

  16. Serracino-Inglott F, Habib NA, Mathie RT (2001) Hepatic ischemia-reperfusion injury. Am J Surg 181(2):160–166

    Article  PubMed  CAS  Google Scholar 

  17. Burroughs AK, Sabin CA, Rolles K et al (2006) 3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome. Lancet 367(9506):225–232

    Article  PubMed  Google Scholar 

  18. Zhong Z, Ramshesh VK, Rehman H et al (2008) Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 295(4):G823–G832

    Article  PubMed  CAS  Google Scholar 

  19. Bernhardt WM, Campean V, Kany S et al (2006) Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol 17(7):1970–1978

    Article  PubMed  CAS  Google Scholar 

  20. Hill P, Shukla D, Tran MG, Aragones J, Cook HT, Carmeliet P, Maxwell PH (2008) Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J Am Soc Nephrol 19(1):39–46

    Article  PubMed  CAS  Google Scholar 

  21. Wang Z, Schley G, Turkoglu G et al (2011) The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment. Nephrol Dial Transplant (in press)

  22. Bernhardt WM, Gottmann U, Doyon F et al (2009) Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model. Proc Natl Acad Sci U S A 106(50):21276–21281

    Article  PubMed  CAS  Google Scholar 

  23. Vollmar B, Menger MD (2011) Intestinal ischemia/reperfusion: microcirculatory pathology and functional consequences. Langenbecks Arch Surg 396(1):13–29

    Article  PubMed  Google Scholar 

  24. Hart ML, Grenz A, Gorzolla IC, Schittenhelm J, Dalton JH, Eltzschig HK (2011) Hypoxia-inducible factor-1alpha-dependent protection from intestinal ischemia/reperfusion injury involves ecto-5′-nucleotidase (CD73) and the A2B adenosine receptor. J Immunol 186(7):4367–4374

    Article  PubMed  CAS  Google Scholar 

  25. Kannan KB, Colorado I, Reino D et al (2011) Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury. Am J Physiol Gastrointest Liver Physiol 300(5):G853–G861

    Article  PubMed  CAS  Google Scholar 

  26. Cramer T, Yamanishi Y, Clausen BE et al (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5):645–657

    Article  PubMed  CAS  Google Scholar 

  27. Peyssonnaux C, Datta V, Cramer T et al (2005) HIF-1alpha expression regulates the bactericidal capacity of phagocytes. J Clin Invest 115(7):1806–1815

    Article  PubMed  CAS  Google Scholar 

  28. Kim HY, Kim YH, Nam BH et al (2007) HIF-1alpha expression in response to lipopolysaccharide mediates induction of hepatic inflammatory cytokine TNF alpha. Exp Cell Res 313(9):1866–1876

    Article  PubMed  CAS  Google Scholar 

  29. Walmsley SR, Chilvers ER, Thompson AA et al (2011) Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. J Clin Invest 121(3):1053–1063

    Article  PubMed  CAS  Google Scholar 

  30. Imtiyaz HZ, Williams EP, Hickey MM et al (2010) Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 120(8):2699–2714

    Article  PubMed  CAS  Google Scholar 

  31. Zinkernagel AS, Johnson RS, Nizet V (2007) Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med 85(12):1339–1346

    Article  PubMed  CAS  Google Scholar 

  32. Gale DP, Maxwell PH (2010) The role of HIF in immunity. Int J Biochem Cell Biol 42(4):486–494

    Article  PubMed  CAS  Google Scholar 

  33. Acosta-Iborra B, Elorza A, Olazabal IM et al (2009) Macrophage oxygen sensing modulates antigen presentation and phagocytic functions involving IFN-gamma production through the HIF-1 alpha transcription factor. J Immunol 182(5):3155–3164

    Article  PubMed  CAS  Google Scholar 

  34. Burke B, Tang N, Corke KP, Tazzyman D, Ameri K, Wells M, Lewis CE (2002) Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy. J Pathol 196(2):204–212

    Article  PubMed  CAS  Google Scholar 

  35. Nizet V, Johnson RS (2009) Interdependence of hypoxic and innate immune responses. Nat Rev Immunol 9(9):609–617

    Article  PubMed  CAS  Google Scholar 

  36. Murdoch C, Muthana M, Lewis CE (2005) Hypoxia regulates macrophage functions in inflammation. J Immunol 175(10):6257–6263

    PubMed  CAS  Google Scholar 

  37. Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364(7):656–665

    Article  PubMed  CAS  Google Scholar 

  38. Vallabhapurapu S, Karin M (2009) Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27:693–733

    Article  PubMed  CAS  Google Scholar 

  39. Kuhlicke J, Frick JS, Morote-Garcia JC, Rosenberger P, Eltzschig HK (2007) Hypoxia inducible factor (HIF)-1 coordinates induction of Toll-like receptors TLR2 and TLR6 during hypoxia. PLoS One 2(12):e1364

    Article  PubMed  Google Scholar 

  40. Walmsley SR, Print C, Farahi N et al (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201(1):105–115

    Article  PubMed  CAS  Google Scholar 

  41. Rius J, Guma M, Schachtrup C et al (2008) NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453(7196):807–811

    Article  PubMed  CAS  Google Scholar 

  42. Takeda Y, Costa S, Delamarre E et al (2011) Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 479(7371):122–126

    Article  PubMed  CAS  Google Scholar 

  43. Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V (2007) Cutting edge: essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol 178(12):7516–7519

    PubMed  CAS  Google Scholar 

  44. Cummins EP, Berra E, Comerford KM et al (2006) Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A 103(48):18154–18159

    Article  PubMed  CAS  Google Scholar 

  45. Xue J, Li X, Jiao S, Wei Y, Wu G, Fang J (2010) Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKbeta independent of hydroxylase activity. Gastroenterology 138(2):606–615

    Article  PubMed  CAS  Google Scholar 

  46. Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347(6):417–429

    Article  PubMed  CAS  Google Scholar 

  47. Maul J, Zeitz M (2012) Ulcerative colitis: immune function, tissue fibrosis and current therapeutic considerations. Langenbecks Arch Surg 397(1):1–10

    Article  PubMed  Google Scholar 

  48. Rutgeerts P, Vermeire S, Van Assche G (2009) Biological therapies for inflammatory bowel diseases. Gastroenterology 136(4):1182–1197

    Article  PubMed  CAS  Google Scholar 

  49. Taylor CT, Colgan SP (2007) Hypoxia and gastrointestinal disease. J Mol Med (Berl) 85(12):1295–1300

    Article  Google Scholar 

  50. Giatromanolaki A, Sivridis E, Maltezos E et al (2003) Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol 56(3):209–213

    Article  PubMed  CAS  Google Scholar 

  51. Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH (2004) Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 114(8):1098–1106

    PubMed  CAS  Google Scholar 

  52. Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ, Fallon PG, Taylor CT (2008) The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134(1):156–165

    Article  PubMed  CAS  Google Scholar 

  53. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev 3(10):721–732

    Article  CAS  Google Scholar 

  54. Zhong H, De Marzo AM, Laughner E et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59(22):5830–5835

    PubMed  CAS  Google Scholar 

  55. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62

    Article  PubMed  CAS  Google Scholar 

  56. Erez N, Milyavsky M, Eilam R, Shats I, Goldfinger N, Rotter V (2003) Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth. Cancer Res 63(24):8777–8783

    PubMed  CAS  Google Scholar 

  57. Su Y, Loos M, Giese N et al (2012) Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. Cancer 118(4):960–972

    Article  PubMed  CAS  Google Scholar 

  58. Chan DA, Kawahara TL, Sutphin PD, Chang HY, Chi JT, Giaccia AJ (2009) Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell 15(6):527–538

    Article  PubMed  CAS  Google Scholar 

  59. Ameln AK, Muschter A, Mamlouk S et al (2011) Inhibition of HIF prolyl hydroxylase-2 blocks tumor growth in mice through the antiproliferative activity of TGFbeta. Cancer Res 71(9):3306–3316

    Article  PubMed  Google Scholar 

  60. Hogel H, Rantanen K, Jokilehto T, Grenman R, Jaakkola PM (2011) Prolyl Hydroxylase PHD3 enhances the hypoxic survival and G1 to S transition of carcinoma cells. PLoS One 6(11):e27112

    Article  PubMed  CAS  Google Scholar 

  61. Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117(5):1155–1166

    Article  PubMed  CAS  Google Scholar 

  62. Lewis C, Murdoch C (2005) Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 167(3):627–635

    Article  PubMed  CAS  Google Scholar 

  63. Mazzone M, Dettori D, Leite de Oliveira R et al (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136(5):839–851

    Article  PubMed  CAS  Google Scholar 

  64. Fraisl P, Aragones J, Carmeliet P (2009) Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov 8(2):139–152

    Article  PubMed  CAS  Google Scholar 

  65. Bernhardt WM, Wiesener MS, Scigalla P, Chou J, Schmieder RE, Gunzler V, Eckardt KU (2010) Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 21(12):2151–2156

    Article  PubMed  CAS  Google Scholar 

  66. Takeda K, Aguila HL, Parikh NS et al (2008) Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood 111(6):3229–3235

    Article  PubMed  CAS  Google Scholar 

  67. Bishop T, Gallagher D, Pascual A et al (2008) Abnormal sympathoadrenal development and systemic hypotension in PHD3−/− mice. Mol Cell Biol 28(10):3386–3400

    Article  PubMed  CAS  Google Scholar 

  68. Kinoshita M, Uchida T, Nakashima H, Ono S, Seki S, Hiraide H (2005) Opposite effects of enhanced tumor necrosis factor-alpha production from Kupffer cells by gadolinium chloride on liver injury/mortality in endotoxemia of normal and partially hepatectomized mice. Shock 23(1):65–72

    Article  PubMed  CAS  Google Scholar 

Download references

Conflicts of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin Schneider.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kiss, J., Kirchberg, J. & Schneider, M. Molecular oxygen sensing: implications for visceral surgery. Langenbecks Arch Surg 397, 603–610 (2012). https://doi.org/10.1007/s00423-012-0930-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00423-012-0930-z

Keywords

Navigation