Skip to main content

Advertisement

SpringerLink
Log in

The heme oxygenase – carbon monoxide system: regulation and role in stress response and organ failure

  • Mini Series: Basic research-related topics
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Heme oxygenase (HO) breaks down heme, the iron-containing, oxygen-carrying constituent of red blood cells, yielding biliverdin, iron (II) ions, and carbon monoxide (CO). Among the isoenzymes cloned to date, only HO-1 can be induced by a panoply of stimuli linked by their ability to provoke oxidative stress. HO-1 induction protects against cell death in experimental models associated with ischemia/reperfusion or inflammation, making the gene a promising target for critical care medicine. Induction of HO-1 may confer protection by controlling intracellular levels of toxic heme, or by anti-inflammatory, anti-apoptotic, and blood flow-maintaining effects of its by-products biliverdin and CO. Although protective effects of upregulation of HO-1 have been reported for a variety of cells and tissues, evidence suggests that the protective action may be restricted to a rather narrow threshold of overexpression. In addition, there is substantial variation in gene expression depending on transcriptional control mechanisms such as a microsatellite length polymorphism. Genetic variability and the required use of cytotoxic inducers are hurdles for purposeful targeting of HO-1 gene expression in critical care, while administration of by-products of the pathway seems feasible at present.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Notes

  1. The HGNC approved gene symbols for the two isoenzymes are HMOX1 (alias HO-1 and bK286B10) and HMOX2 (alias HO-2) respectively, thus we use HO-1 and HO-2 for convenience throughout the manuscript.

References

  1. Maines MD (1992) Heme oxygenase. Clinical applications and functions. CRC Press, Boca Raton, FL

    Google Scholar 

  2. Balla G, Vercellotti GM, Muller-Eberhard U, Eaton J, Jacob HS (1991) Exposure of endothelial cells to free heme potentiates damage mediated by granulocytes and toxic oxygen species. Lab Invest 64:648–655

    PubMed  CAS  Google Scholar 

  3. Gutteridge JM, Smith A (1988) Antioxidant protection by haemopexin of haem-stimulated lipid peroxidation. Biochem J 256:861–865

    PubMed  CAS  Google Scholar 

  4. Ryter SW, Tyrrell RM (2000) The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. Free Radic Biol Med 28:289–309

    Article  PubMed  CAS  Google Scholar 

  5. Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61:748–755

    Article  PubMed  CAS  Google Scholar 

  6. Elbirt KK, Bonkovsky HL (1999) Heme oxygenase: recent advances in understanding its regulation and role. Proc Assoc Am Physicians 111:438–447

    PubMed  CAS  Google Scholar 

  7. Kutty RK, Maines MD (1981) Purification and characterization of biliverdin reductase from rat liver. J Biol Chem 256:3956–3962

    PubMed  CAS  Google Scholar 

  8. Maines MD (1997) The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37:517–554

    Article  PubMed  CAS  Google Scholar 

  9. Suematsu M, Wakabayashi Y, Ishimura Y (1996) Gaseous monoxides: a new class of microvascular regulator in the liver. Cardiovasc Res 32:679–686

    Article  PubMed  CAS  Google Scholar 

  10. Naik JS, Walker BR (2003) Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization. Am J Physiol Heart Circ Physiol 285:H2, 20–28

    Google Scholar 

  11. Hosein S, Marks GS, Brien JF, McLaughlin BE, Nakatsu K (2002) An extracellular source of heme can induce a significant heme oxygenase mediated relaxation in the rat aorta. Can J Physiol Pharmacol 80:761–765

    Article  PubMed  CAS  Google Scholar 

  12. Zhang F, Kaide J, Wei Y, Jiang H, Yu C, Balazy M, Abraham NG, Wang W, Nasjletti A (2001) Carbon monoxide produced by isolated arterioles attenuates pressure-induced vasoconstriction. Am J Physiol Heart Circ Physiol 281:H350–358

    PubMed  CAS  Google Scholar 

  13. Wu L, Wang R (2005) Carbon monoxide: endogenous production, physiological functions, and pharmacological applications. Pharmacol Rev 57:585–630

    Article  PubMed  CAS  Google Scholar 

  14. Wang R, Wu L (1997) The chemical modification of KCa channels by carbon monoxide in vascular smooth muscle cells. J Biol Chem 272:8222–8226

    Article  PubMed  CAS  Google Scholar 

  15. Tang XD, Xu R, Reynolds MF, Garcia ML, Heinemann SH, Hoshi T (2003) Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425:531–535

    Article  PubMed  CAS  Google Scholar 

  16. Jaggar JH, Li A, Parfenova H, Liu J, Umstot ES, Dopico AM, Leffler CW (2005) Heme is a carbon monoxide receptor for large-conductance Ca2+-activated K+ channels. Circ Res 97:805–812

    Article  PubMed  CAS  Google Scholar 

  17. Xi Q, Tcheranova D, Parfenova H, Horowitz B, Leffler CW, Jaggar JH (2004) Carbon monoxide activates KCa channels in newborn arteriole smooth muscle cells by increasing apparent Ca2+ sensitivity of alpha-subunits. Am J Physiol Heart Circ Physiol 286:H610–618

    Article  PubMed  CAS  Google Scholar 

  18. Jaggar JH, Porter VA, Lederer WJ, Nelson MT (2000) Calcium sparks in smooth muscle. Am J Physiol Cell Physiol 278:C235–256

    PubMed  CAS  Google Scholar 

  19. Jaggar JH, Leffler CW, Cheranov SY, Tcheranova D, Shuyu E, Cheng X (2002) Carbon monoxide dilates cerebral arterioles by enhancing the coupling of Ca2+ sparks to Ca2+-activated K+ channels. Circ Res 91:610–617

    Article  PubMed  CAS  Google Scholar 

  20. Vreman HJ, Stevenson DK (1988) Heme oxygenase activity as measured by carbon monoxide production. Anal Biochem 168:31–38

    Article  PubMed  CAS  Google Scholar 

  21. Maines MD (1988) Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J 2:2557–2568

    PubMed  CAS  Google Scholar 

  22. Cruse I, Maines MD (1988) Evidence suggesting that the two forms of heme oxygenase are products of different genes. J Biol Chem 263:3348–3353

    PubMed  CAS  Google Scholar 

  23. McCoubrey WK Jr, Huang TJ, Maines MD (1997) Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem 247:725–732

    Article  PubMed  CAS  Google Scholar 

  24. Shibahara S, Muller R, Taguchi H, Yoshida T (1985) Cloning and expression of cDNA for rat heme oxygenase. Proc Natl Acad Sci USA 82:7865–7869

    Article  PubMed  CAS  Google Scholar 

  25. Shibahara S, Yoshizawa M, Suzuki H, Takeda K, Meguro K, Endo K (1993) Functional analysis of cDNAs for two types of human heme oxygenase and evidence for their separate regulation. J Biochem 113:214–218

    PubMed  CAS  Google Scholar 

  26. Hayashi S, Omata Y, Sakamoto H, Higashimoto Y, Hara T, Sagara Y, Noguchi M (2004) Characterization of rat heme oxygenase-3 gene. Implication of processed pseudogenes derived from heme oxygenase-2 gene. Gene 336:241–250

    Article  PubMed  CAS  Google Scholar 

  27. Kutty RK, Kutty G, Rodriguez IR, Chader GJ, Wiggert B (1994) Chromosomal localization of the human heme oxygenase genes: heme oxygenase-1 (HMOX1) maps to chromosome 22q12 and heme oxygenase-2 (HMOX2) maps to chromosome 16p13.3. Genomics 20:513–516

    Article  PubMed  CAS  Google Scholar 

  28. Kuwano A, Ikeda H, Takeda K, Nakai H, Kondo I, Shibahara S (1994) Mapping of the human gene for inducible heme oxygenase to chromosome 22q12. Tohoku J Exp Med 172:389–392

    Article  PubMed  CAS  Google Scholar 

  29. Trakshel GM, Maines MD (1989) Multiplicity of heme oxygenase isozymes. HO-1 and HO-2 are different molecular species in rat and rabbit. J Biol Chem 264:1323–1328

    PubMed  CAS  Google Scholar 

  30. Bauer I, Wanner GA, Rensing H, Alte C, Miescher EA, Wolf B, Pannen BH, Clemens MG, Bauer M (1998) Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver. Hepatology 27:829–838

    Article  PubMed  CAS  Google Scholar 

  31. Maines MD, Eke BC, Zhao X (1996) Corticosterone promotes increased heme oxygenase-2 protein and transcript expression in the newborn rat brain. Brain Res 722:83–94

    Article  PubMed  CAS  Google Scholar 

  32. Sonin NV, Garcia-Pagan JC, Nakanishi K, Zhang JX, Clemens MG (1999) Patterns of vasoregulatory gene expression in the liver response to ischemia/reperfusion and endotoxemia. Shock 11:175–179

    Article  PubMed  CAS  Google Scholar 

  33. Shibahara S, Muller RM, Taguchi H (1987) Transcriptional control of rat heme oxygenase by heat shock. J Biol Chem 262:12889–12892

    PubMed  CAS  Google Scholar 

  34. Bauer I, Rensing H, Florax A, Ulrich C, Pistorius G, Redl H, Bauer M (2003) Expression pattern and regulation of heme oxygenase-1/heat shock protein 32 in human liver cells. Shock 20:116–122

    Article  PubMed  CAS  Google Scholar 

  35. Bauer M (2003) Heme oxygenase in liver transplantation: heme catabolism and metabolites in the search of function. Hepatology 38:286–288

    Article  PubMed  Google Scholar 

  36. Mayr FB, Spiel A, Leitner J, Marsik C, Germann P, Ullrich R, Wagner O, Jilma B (2005) Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am J Respir Crit Care Med 171:354–360

    Article  PubMed  Google Scholar 

  37. Bauer M, Bauer I (2002) Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative stress. Antioxid Redox Signal 4:749–758

    Article  PubMed  CAS  Google Scholar 

  38. Shan Y, Lambrecht RW, Ghaziani T, Donohue SE, Bonkovsky HL (2004) Role of Bach-1 in regulation of heme oxygenase-1 in human liver cells: insights from studies with small interfering RNAS. J Biol Chem 279:51769–51774

    Article  PubMed  CAS  Google Scholar 

  39. Deramaudt TB, da Silva JL, Remy P, Kappas A, Abraham NG (1999) Negative regulation of human heme oxygenase in microvessel endothelial cells by dexamethasone. Proc Soc Exp Biol Med 222:185–193

    Article  PubMed  CAS  Google Scholar 

  40. Grosser N, Hemmerle A, Berndt G, Erdmann K, Hinkelmann U, Schurger S, Wijayanti N, Immenschuh S, Schroder H (2004) The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med 37:2064–2071

    Article  PubMed  CAS  Google Scholar 

  41. Rensing H, Bauer I, Kubulus D, Wolf B, Winning J, Ziegeler S, Bauer M (2004) Heme oxygenase-1 gene expression in pericentral hepatocytes through beta1-adrenoceptor stimulation. Shock 21:376–387

    Article  PubMed  CAS  Google Scholar 

  42. Raddatz A, Kubulus D, Winning J, Bauer I, Pradarutti S, Wolf B, Kreuer S, Rensing H (2006) Dobutamine improves liver function after hemorrhagic shock through induction of heme oxygenase-1. Am J Respir Crit Care Med 174:198–207

    Article  PubMed  CAS  Google Scholar 

  43. Kubulus D, Rensing H, Paxian M, Thierbach JT, Meisel T, Redl H, Bauer M, Bauer I (2005) Influence of heme-based solutions on stress protein expression and organ failure after hemorrhagic shock. Crit Care Med 33:629–637

    Article  PubMed  CAS  Google Scholar 

  44. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235:1043–1046

    Article  PubMed  CAS  Google Scholar 

  45. Suematsu M, Goda N, Sano T, Kashiwagi S, Egawa T, Shinoda Y, Ishimura Y (1995) Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver. J Clin Invest 96:2431–2437

    Article  PubMed  CAS  Google Scholar 

  46. Bauer M, Pannen BH, Bauer I, Herzog C, Wanner GA, Hanselmann R, Zhang JX, Clemens MG, Larsen R (1996) Evidence for a functional link between stress response and vascular control in hepatic portal circulation. Am J Physiol 271:G929–935

    PubMed  CAS  Google Scholar 

  47. Applegate LA, Luscher P, Tyrrell RM (1991) Induction of heme oxygenase: a general response to oxidant stress in cultured mammalian cells. Cancer Res 51:974–978

    PubMed  CAS  Google Scholar 

  48. Paxian M, Rensing H, Rickauer A, Schonhofen S, Schmeck J, Pannen BH, Bauer I, Bauer M (2001) Kupffer cells and neutrophils as paracrine regulators of the heme oxygenase-1 gene in hepatocytes after hemorrhagic shock. Shock 15:438–445

    PubMed  CAS  Google Scholar 

  49. Rensing H, Bauer I, Peters I, Wein T, Silomon M, Jaeschke H, Bauer M (1999) Role of reactive oxygen species for hepatocellular injury and heme oxygenase-1 gene expression after hemorrhage and resuscitation. Shock 12:300–308

    Article  PubMed  CAS  Google Scholar 

  50. Pannen BH, Kohler N, Hole B, Bauer M, Clemens MG, Geiger KK (1998) Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats. J Clin Invest 102:1220–1228

    Article  PubMed  CAS  Google Scholar 

  51. Rensing H, Bauer I, Datene V, Patau C, Pannen BH, Bauer M (1999) Differential expression pattern of heme oxygenase-1/heat shock protein 32 and nitric oxide synthase-II and their impact on liver injury in a rat model of hemorrhage and resuscitation. Crit Care Med 27:2766–2775

    Article  PubMed  CAS  Google Scholar 

  52. Dennery PA, McDonagh AF, Spitz DR, Rodgers PA, Stevenson DK (1995) Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia. Free Radic Biol Med 19:395–404

    Article  PubMed  CAS  Google Scholar 

  53. Hayashi S, Takamiya R, Yamaguchi T, Matsumoto K, Tojo SJ, Tamatani T, Kitajima M, Makino N, Ishimura Y, Suematsu M (1999) Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme. Circ Res 85:663–671

    PubMed  CAS  Google Scholar 

  54. Stocker R, McDonagh AF, Glazer AN, Ames BN (1990) Antioxidant activities of bile pigments: biliverdin and bilirubin. Methods Enzymol 186:301–309

    PubMed  CAS  Google Scholar 

  55. Suttner DM, Dennery PA (1999) Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. FASEB J 13:1800–1809

    PubMed  CAS  Google Scholar 

  56. Wennberg RP (1991) Cellular basis of bilirubin toxicity. N Y State J Med 91:493–496

    PubMed  CAS  Google Scholar 

  57. Eisenstein RS (2000) Iron regulatory proteins and the molecular control of mammalian iron metabolism. Annu Rev Nutr 20:627–662

    Article  PubMed  CAS  Google Scholar 

  58. Balla J, Vercellotti GM, Jeney V, Yachie A, Varga Z, Eaton JW, Balla G (2005) Heme, heme oxygenase and ferritin in vascular endothelial cell injury. Mol Nutr Food Res 49:1030–1043

    Article  PubMed  CAS  Google Scholar 

  59. Dennery PA, Spitz DR, Yang G, Tatarov A, Lee CS, Shegog ML, Poss KD (1998) Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. J Clin Invest 101:1001–1011

    Article  PubMed  CAS  Google Scholar 

  60. Ryter SW, Si M, Lai CC, Su CY (2000) Regulation of endothelial heme oxygenase activity during hypoxia is dependent on chelatable iron. Am J Physiol Heart Circ Physiol 279:H2889–2897

    PubMed  CAS  Google Scholar 

  61. Poss KD, Tonegawa S (1997) Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 94:10919–10924

    Article  PubMed  CAS  Google Scholar 

  62. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103:129–135

    Article  PubMed  CAS  Google Scholar 

  63. Kawashima A, Oda Y, Yachie A, Koizumi S, Nakanishi I (2002) Heme oxygenase-1 deficiency: the first autopsy case. Hum Pathol 33:125–130

    Article  PubMed  Google Scholar 

  64. Ingi T, Cheng J, Ronnett GV (1996) Carbon monoxide: an endogenous modulator of the nitric oxide-cyclic GMP signaling system. Neuron 16:835–842

    Article  PubMed  CAS  Google Scholar 

  65. Hartsfield CL (2002) Cross talk between carbon monoxide and nitric oxide. Antioxid Redox Signal 4:301–307

    Article  PubMed  CAS  Google Scholar 

  66. Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH (1993) Carbon monoxide: a putative neural messenger. Science 259:381–384

    Article  PubMed  CAS  Google Scholar 

  67. Baranano DE, Ferris CD, Snyder SH (2001) Atypical neural messengers. Trends Neurosci 24:99–106

    Article  PubMed  CAS  Google Scholar 

  68. Kharitonov VG, Sharma VS, Pilz RB, Magde D, Koesling D (1995) Basis of guanylate cyclase activation by carbon monoxide. Proc Natl Acad Sci USA 92:2568–2571

    Article  PubMed  CAS  Google Scholar 

  69. Andrew CR, George SJ, Lawson DM, Eady RR (2002) Six- to five-coordinate heme-nitrosyl conversion in cytochrome c' and its relevance to guanylate cyclase. Biochemistry 41:2353–2360

    Article  PubMed  CAS  Google Scholar 

  70. Stone JR, Marletta MA (1994) Soluble guanylate cyclase from bovine lung: activation with nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states. Biochemistry 33:5636–5640

    Article  PubMed  CAS  Google Scholar 

  71. Friebe A, Schultz G, Koessling D (1996) Sensitizing soluble guanylate cyclase to become a highly CO-sensitive enzyme. EMBO J 15:6835–6868

    Google Scholar 

  72. Xue L, Farrugia G, Miller SM, Ferris CD, Snyder SH, Szurszewski JH (2000) Carbon monoxide and nitric oxide as coneurotransmitters in the enteric nervous system: evidence from genomic deletion of biosynthetic enzymes. Proc Natl Acad Sci USA 97:1851–1855

    Article  PubMed  CAS  Google Scholar 

  73. Kweon MH, Park YI, Sung HC, Mukhtar H (2006) The novel antioxidant 3-O-caffeoyl-1-methylquinic acid induces Nrf2-dependent phase II detoxifying genes and alters intracellular glutathione redox. Free Radic Biol Med 40:1349–1361

    Article  PubMed  CAS  Google Scholar 

  74. Ryter SW, Choi AM (2002) Heme oxygenase-1: molecular mechanisms of gene expression in oxygen-related stress. Antioxid Redox Signal 4:625–632

    Article  PubMed  CAS  Google Scholar 

  75. Chang SH, Garcia J, Melendez JA, Kilberg MS, Agarwal A (2003) Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain. Biochem J 371:877–885

    Article  PubMed  CAS  Google Scholar 

  76. Suh GY, Jin Y, Yi AK, Wang XM, Choi AM (2006) CCAAT/enhancer-binding Protein Mediates Carbon Monoxide-induced Suppression of Cyclooxygenase-2. Am J Respir Cell Mol Biol 35:220–226

    Article  PubMed  CAS  Google Scholar 

  77. Rensing H, Bauer I, Zhang JX, Paxian M, Pannen BH, Yokoyama Y, Clemens MG, Bauer M (2002) Endothelin-1 and heme oxygenase-1 as modulators of sinusoidal tone in the stress-exposed rat liver. Hepatology 36:1453–1465

    PubMed  CAS  Google Scholar 

  78. Sarady JK, Zuckerbraun BS, Bilban M, Wagner O, Usheva A, Liu F, Ifedigbo E, Zamora R, Choi AM, Otterbein LE (2004) Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J 18:854–856

    PubMed  Google Scholar 

  79. Wang R, Wu L, Wang Z (1997) The direct effect of carbon monoxide on KCa channels in vascular smooth muscle cells. Pflugers Arch 434:285–291

    Article  PubMed  CAS  Google Scholar 

  80. Kaide JI, Zhang F, Wei Y, Jiang H, Yu C, Wang WH, Balazy M, Abraham NG, Nasjletti A (2001) Carbon monoxide of vascular origin attenuates the sensitivity of renal arterial vessels to vasoconstrictors. J Clin Invest 107:1163–1171

    Article  PubMed  CAS  Google Scholar 

  81. Tsuburai T, Suzuki M, Nagashima Y, Suzuki S, Inoue S, Hasiba T, Ueda A, Ikehara K, Matsuse T, Ishigatsubo Y (2002) Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin-induced pulmonary fibrosis via a Fas-Fas ligand-independent pathway. Hum Gene Ther 13:1945–1960

    Article  PubMed  CAS  Google Scholar 

  82. Desmard M, Amara N, Lanone S, Motterlini R, Boczkowski J (2005) Carbon monoxide reduces the expression and activity of matrix metalloproteinases 1 and 2 in alveolar epithelial cells. Cell Mol Biol (Noisy-le-grand) 51:403–408

    CAS  Google Scholar 

  83. Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6:422–428

    Article  PubMed  CAS  Google Scholar 

  84. Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, Chung KR, Chung HAT (2004) Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol 172:4744–4751

    PubMed  CAS  Google Scholar 

  85. Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94:10925–10930

    Article  PubMed  CAS  Google Scholar 

  86. Amersi F, Buelow R, Kato H, Ke B, Coito AJ, Shen XD, Zhao D, Zaky J, Melinek J, Lassman CR, Kolls JK, Alam J, Ritter T, Volk HD, Farmer DG, Ghobrial RM, Busuttil RW, Kupiec-Weglinski JW (1999) Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest 104:1631–1639

    Article  PubMed  CAS  Google Scholar 

  87. Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6:422–428

    Article  PubMed  CAS  Google Scholar 

  88. Yu HP, Choudhry MA, Shimizu T, Hsieh YC, Schwacha MG, Yang S, Chaudry IH (2006) Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor-{beta}-dependent HO-1. J Leukoc Biol 79:277–284

    Article  PubMed  CAS  Google Scholar 

  89. Sarady-Andrews JK, Liu F, Gallo D, Nakao A, Overhaus M, Ollinger R, Choi AM, Otterbein LE (2005) Biliverdin administration protects against endotoxin-induced acute lung injury in rats. Am J Physiol Lung Cell Mol Physiol 289:L1131–1137

    Article  PubMed  CAS  Google Scholar 

  90. Gorbunov NV, Asher LV, Ayyagari V, Atkins JL (2006) Inflammatory leukocytes and iron turnover in experimental hemorrhagic lung trauma. Exp Mol Pathol 80:11–25

    PubMed  CAS  Google Scholar 

  91. Akagi R, Takahashi T, Sassa S (2005) Cytoprotective effects of heme oxygenase in acute renal failure. Contrib Nephrol 148:70–85

    PubMed  CAS  Google Scholar 

  92. Wunder C, Brock RW, Frantz S, Gottsch W, Morawietz H, Roewer N, Eichelbronner O (2005) Carbon monoxide, but not endothelin-1, plays a major role for the hepatic microcirculation in a murine model of early systemic inflammation. Crit Care Med 33:2323–2331

    Article  PubMed  CAS  Google Scholar 

  93. Willis D, Moore AR, Frederick R, Willoughby DA (1996) Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med 2:87–90

    Article  PubMed  CAS  Google Scholar 

  94. HMOX2 locus is found in the human genome assembly hg18 at chr16:4,466,447–4,500,348

  95. Texereau J, Marullo S, Hubert D, Coste J, Dusser DJ, Dall'Ava-Santucci J, Dinh-Xuan AT (2004) Nitric oxide synthase 1 as a potential modifier gene of decline in lung function in patients with cystic fibrosis. Thorax 59:156–158

    Article  PubMed  CAS  Google Scholar 

  96. Myers SJ, Huang Y, Genetta T, Dingledine R (2004) Inhibition of glutamate receptor 2 translation by a polymorphic repeat sequence in the 5′-untranslated leaders. J Neurosci 24:3489–3499

    Article  PubMed  CAS  Google Scholar 

  97. Dick P, Schillinger M, Minar E, Mlekusch W, Amighi J, Sabeti S, Schlager O, Raith M, Endler G, Mannhalter C, Wagner O, Exner M (2005) Haem oxygenase-1 genotype and cardiovascular adverse events in patients with peripheral artery disease. Eur J Clin Invest 35:731–737

    Article  PubMed  CAS  Google Scholar 

  98. Li P, Elrayess MA, Gomma AH, Palmen J, Hawe E, Fox KM, Humphries SE (2005) The microsatellite polymorphism of heme oxygenase-1 is associated with baseline plasma IL-6 level but not with restenosis after coronary in-stenting. Chin Med J (Engl) 118:1525–1532

    CAS  Google Scholar 

  99. Ullrich R, Exner M, Schillinger M, Zuckermann A, Raith M, Dunkler D, Horvat R, Grimm M, Wagner O (2005) Microsatellite polymorphism in the heme oxygenase-1 gene promoter and cardiac allograft vasculopathy. J Heart Lung Transplant 24:1600–1605

    Article  PubMed  Google Scholar 

  100. Li P, Sanders J, Hawe E, Brull D, Montgomery H, Humphries S (2005) Inflammatory response to coronary artery bypass surgery: does the heme-oxygenase-1 gene microsatellite polymorphism play a role? Chin Med J (Engl) 118:1285–1290

    CAS  Google Scholar 

  101. Geuken E, Buis CI, Visser DS, Blokzijl H, Moshage H, Nemes B, Leuvenink HG, de Jong KP, Peeters PM, Slooff MJ, Porte RJ (2005) Expression of heme oxygenase-1 in human livers before transplantation correlates with graft injury and function after transplantation. Am J Transplant 5:1875–1885

    Article  PubMed  CAS  Google Scholar 

  102. Exner M, Bohmig GA, Schillinger M, Regele H, Watschinger B, Horl WH, Raith M, Mannhalter C, Wagner OF (2004) Donor heme oxygenase-1 genotype is associated with renal allograft function. Transplantation 77:538–542

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care Medicine, Friedrich Schiller University Hospital, Erlanger Allee 101, 07740, Jena, Germany

    Michael Bauer & Ralf A. Claus

  2. Leibniz Institute for Age Research – Fritz Lipmann Institute, Jena, Germany

    Klaus Huse

  3. Department of General, Visceral, and Vascular Surgery, Friedrich Schiller University Hospital, Jena, Germany

    Utz Settmacher

Authors
  1. Michael Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Klaus Huse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Utz Settmacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ralf A. Claus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Bauer.

Additional information

This article is discussed in the editorial available at: http://dx.doi.org/10.1007/s00134-008-1013-z.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bauer, M., Huse, K., Settmacher, U. et al. The heme oxygenase – carbon monoxide system: regulation and role in stress response and organ failure. Intensive Care Med 34, 640–648 (2008). https://doi.org/10.1007/s00134-008-1010-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-008-1010-2

Keywords

Search

Navigation