Home LiteratureArticle Details
PMID: 14766943 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S. Review

The role of carbon monoxide in the gastrointestinal tract.

The Journal of physiology ·Vol. 556 ·No. Pt 2 ·2004-04-15 ·Pages 325-36

Gibbons SJ, Farrugia G

Abstract

Carbon monoxide (CO) is a biologically active product of haem metabolism that contributes to the normal physiology of the gastrointestinal tract. In this article, we review recent data showing that CO is an integral regulator of gastrointestinal motility and an important factor in the response to gastrointestinal injury. CO is generated by haem oxygenase-2 (HO-2), which is constitutively expressed in many inhibitory neurones of the vertebrate enteric nervous system. The membrane potential gradients along and across the muscle layers of the gastrointestinal tract require the generation of CO by haem oxygenase-2. The presence of CO is also necessary for normal inhibitory neurotransmission in circular smooth muscle and appears to permit nitric oxide-mediated inhibitory neurotransmission. Genetic deletion of the haem oxygenase-2 gene in mice slows gut transit. The other major CO synthetic enzyme, haem oxygenase-1 (HO-1) is induced under conditions of stress or injury. Recent studies have demonstrated that up-regulation of haem oxygenase-1 protects the gut from several types of gastrointestinal injury, suggesting that CO or induction of HO-1 may find therapeutic use in gastrointestinal diseases and injuries. Furthermore, it is anticipated that the understanding of CO-mediated signalling in the gastrointestinal tract will inform studies in other tissues that express haem oxygenases.

MeSH Terms
Animals Carbon Monoxide/physiology Gastrointestinal Tract/physiology Humans
Chemicals
Carbon Monoxide
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Gibbons Simon J
Enteric Neuroscience Program, Mayo Clinic Rochester, 200 First Street SW, Rochester MN 55905, USA.
Farrugia Gianrico
References (100)
100 references, click to expand
  1. Mechanisms underlying induction of heme oxygenase-1 by nitric oxide in renal tubular epithelial cells.
    Am J Physiol Renal Physiol. 2000 Oct;279(4):F728-35 PMID: 10997923
  2. Novel neurotransmitters and their neuropsychiatric relevance.
    Am J Psychiatry. 2000 Nov;157(11):1738-51 PMID: 11058466
  3. Inhibition of inducible nitric oxide synthase in the human intestinal epithelial cell line, DLD-1, by the inducers of heme oxygenase 1, bismuth salts, heme, and nitric oxide donors.
    Gut. 2000 Dec;47(6):771-8 PMID: 11076874
  4. Real-time measurements of endogenous CO production from vascular cells using an ultrasensitive laser sensor.
    Am J Physiol Heart Circ Physiol. 2001 Jan;280(1):H483-8 PMID: 11123266
  5. Haem oxygenase in enteric nervous system of human stomach and jejunum and co-localization with nitric oxide synthase.
    Neurogastroenterol Motil. 2001 Apr;13(2):121-31 PMID: 11298990
  6. The case of CO signaling: why the jury is still out.
    J Clin Invest. 2001 May;107(9):1071-3 PMID: 11342568
  7. Protective role of heme oxygenase-1 on trinitrobenzene sulfonic acid-induced colitis in rats.
    Am J Physiol Gastrointest Liver Physiol. 2001 Aug;281(2):G586-94 PMID: 11447040
  8. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia.
    Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8798-803 PMID: 11447290
  9. Stereologic description of the changing expression of constitutive nitric oxide synthase and heme oxygenase in the enteric plexuses of the pig small intestine during development.
    J Comp Neurol. 2001 Aug 13;437(1):118-28 PMID: 11477601
  10. Carbon monoxide-dependent signaling.
    Crit Care Med. 2002 Jan;30(1 Suppl):S12-7 PMID: 11782556
  11. Immunohistochemical localization of the antioxidant enzymes biliverdin reductase and heme oxygenase-2 in human and pig gastric fundus.
    Free Radic Biol Med. 2002 Apr 1;32(7):630-7 PMID: 11909697
  12. Emerging role of carbon monoxide in physiologic and pathophysiologic states.
    Antioxid Redox Signal. 2002 Apr;4(2):227-8 PMID: 12006173
  13. Biological chemistry of carbon monoxide.
    Antioxid Redox Signal. 2002 Apr;4(2):259-70 PMID: 12006177
  14. Measurement of endogenous carbon monoxide formation in biological systems.
    Antioxid Redox Signal. 2002 Apr;4(2):271-7 PMID: 12006178
  15. Cerebrovascular effects of carbon monoxide.
    Antioxid Redox Signal. 2002 Apr;4(2):279-90 PMID: 12006179
  16. Hypoxia and carbon monoxide in the vasculature.
    Antioxid Redox Signal. 2002 Apr;4(2):291-9 PMID: 12006180
  17. Cross talk between carbon monoxide and nitric oxide.
    Antioxid Redox Signal. 2002 Apr;4(2):301-7 PMID: 12006181
  18. Modulation of endothelial cell apoptosis by heme oxygenase-1-derived carbon monoxide.
    Antioxid Redox Signal. 2002 Apr;4(2):321-9 PMID: 12006183
  19. Heme oxygenase-1-derived carbon monoxide requires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosis factor-alpha-mediated apoptosis.
    J Biol Chem. 2002 May 17;277(20):17950-61 PMID: 11880364
  20. Heme oxygenase-1, a protective gene that prevents the rejection of transplanted organs.
    Immunol Rev. 2001 Dec;184:275-85 PMID: 12086318
  21. Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients.
    Hum Genet. 2002 Jul;111(1):1-8 PMID: 12136229
  22. Induction of heme oxygenase in guinea-pig stomach: roles in contraction and in single muscle cell ionic currents.
    Acta Physiol Scand. 2002 Aug;175(4):297-313 PMID: 12167169
  23. Protective role of heme oxygenase-1 in the intestinal tissue injury in an experimental model of sepsis.
    Crit Care Med. 2003 Mar;31(3):893-902 PMID: 12627002
  24. Mechanism of glutamate stimulation of CO production in cerebral microvessels.
    Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H74-80 PMID: 12623781
  25. A major role for carbon monoxide as an endogenous hyperpolarizing factor in the gastrointestinal tract.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8567-70 PMID: 12832617
  26. Protective effect of carbon monoxide inhalation for cold-preserved small intestinal grafts.
    Surgery. 2003 Aug;134(2):285-92 PMID: 12947331
  27. Graft protective effects of heme oxygenase 1 in mouse tracheal transplant-related obliterative bronchiolitis.
    Transplantation. 2003 Aug 27;76(4):650-6 PMID: 12973103
  28. Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2.
    Neuron. 2003 Sep 25;40(1):129-37 PMID: 14527438
  29. Regional distribution of the enzymes of haem biosynthesis and the inhibition of 5-aminolaevulinate synthase by manganese in the rat brain.
    Biochem J. 1980 Aug 15;190(2):315-21 PMID: 6894089
  30. Slow wave heterogeneity within the circular muscle of the canine gastric antrum.
    J Physiol. 1985 Sep;366:221-32 PMID: 4057090
  31. Gradient in excitation-contraction coupling in canine gastric antral circular muscle.
    J Physiol. 1985 Dec;369:283-94 PMID: 4093884
  32. Passive and active membrane properties of canine gastric antral circular muscles.
    Am J Physiol. 1986 Aug;251(2 Pt 1):C268-73 PMID: 3740253
  33. Bilirubin is an antioxidant of possible physiological importance.
    Science. 1987 Feb 27;235(4792):1043-6 PMID: 3029864
  34. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.
    Nature. 1987 Jun 11-17;327(6122):524-6 PMID: 3495737
  35. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical.
    Circ Res. 1987 Dec;61(6):866-79 PMID: 2890446
  36. Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity.
    Am J Physiol. 1988 Sep;255(3 Pt 2):F539-44 PMID: 3414810
  37. Heme oxygenase modulates oxidant-signaled airway smooth muscle contractility: role of bilirubin.
    Am J Physiol Lung Cell Mol Physiol. 2002 Sep;283(3):L596-603 PMID: 12169579
  38. Ferritin: a cytoprotective antioxidant strategem of endothelium.
    J Biol Chem. 1992 Sep 5;267(25):18148-53 PMID: 1517245
  39. Activation of whole cell currents in isolated human jejunal circular smooth muscle cells by carbon monoxide.
    Am J Physiol. 1993 Jun;264(6 Pt 1):G1184-9 PMID: 8392811
  40. Carbon monoxide stimulates a potassium-selective current in rabbit corneal epithelial cells.
    Am J Physiol. 1994 Aug;267(2 Pt 1):C435-42 PMID: 8074178
  41. Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms.
    Am J Physiol. 1994 Nov;267(5 Pt 2):H1921-7 PMID: 7526714
  42. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity.
    Nature. 1995 Jan 26;373(6512):347-9 PMID: 7530333
  43. Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine.
    J Physiol. 1994 Oct 1;480 ( Pt 1):91-7 PMID: 7853230
  44. Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP.
    Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1475-9 PMID: 7878003
  45. Carbon monoxide: an endogenous modulator of the nitric oxide-cyclic GMP signaling system.
    Neuron. 1996 Apr;16(4):835-42 PMID: 8608001
  46. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury.
    Am J Respir Cell Mol Biol. 1996 Jul;15(1):9-19 PMID: 8679227
  47. Expression of heme oxygenase-2 (HO-2)-like immunoreactivity in rat tissues.
    Acta Histochem. 1996 Apr;98(2):203-14 PMID: 8739305
  48. Localization and activity of haem oxygenase and functional effects of carbon monoxide in the feline lower oesophageal sphincter.
    Br J Pharmacol. 1996 May;118(2):392-9 PMID: 8735643
  49. Heme oxygenase-2 in primary afferent neurons of the guinea-pig.
    Histochem Cell Biol. 1996 Jun;105(6):453-8 PMID: 8791104
  50. Carbon monoxide-induced relaxation of the ductus arteriosus in the lamb: evidence against the prime role of guanylyl cyclase.
    Br J Pharmacol. 1996 Aug;118(7):1689-96 PMID: 8842433
  51. Sensitizing soluble guanylyl cyclase to become a highly CO-sensitive enzyme.
    EMBO J. 1996 Dec 16;15(24):6863-8 PMID: 9003762
  52. Regulation of heme oxygenase-2 by glucocorticoids in neonatal rat brain: characterization of a functional glucocorticoid response element.
    Biochim Biophys Acta. 1997 Mar 20;1351(1-2):89-104 PMID: 9116047
  53. The heme oxygenase system: a regulator of second messenger gases.
    Annu Rev Pharmacol Toxicol. 1997;37:517-54 PMID: 9131263
  54. Morphological relations between haem oxygenases, NO-synthase and VIP in the canine and feline gastrointestinal tracts.
    J Auton Nerv Syst. 1997 Jul 14;65(1):49-56 PMID: 9258872
  55. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3.
    Eur J Biochem. 1997 Jul 15;247(2):725-32 PMID: 9266719
  56. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.
    J Clin Invest. 1997 Sep 1;100(5):1209-16 PMID: 9276739
  57. Reduced stress defense in heme oxygenase 1-deficient cells.
    Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30 PMID: 9380736
  58. Regulation of heme oxygenase-1 gene expression in vascular smooth muscle cells by nitric oxide.
    Am J Physiol. 1997 Nov;273(5 Pt 1):L980-8 PMID: 9374724
  59. Targeted gene deletion of heme oxygenase 2 reveals neural role for carbon monoxide.
    Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14848-53 PMID: 9405702
  60. Heme oxygenase 2 is present in interstitial cell networks of the mouse small intestine.
    Gastroenterology. 1998 Feb;114(2):239-44 PMID: 9453482
  61. Iron, free radicals, and oxidative injury.
    Semin Hematol. 1998 Jan;35(1):5-12 PMID: 9460805
  62. Distribution of heme oxygenase and effects of exogenous carbon monoxide in canine jejunum.
    Am J Physiol. 1998 Feb;274(2 Pt 1):G350-8 PMID: 9486189
  63. Contribution of carbon monoxide-producing cells in the gastric mucosa of rat and monkey.
    Histochem Cell Biol. 1998 Apr;109(4):369-73 PMID: 9562386
  64. Synergistic activation of soluble guanylate cyclase by YC-1 and carbon monoxide: implications for the role of cleavage of the iron-histidine bond during activation by nitric oxide.
    Chem Biol. 1998 May;5(5):255-61 PMID: 9646941
  65. Endothelium-derived hyperpolarizing factor--a critical appraisal.
    Prog Drug Res. 1998;50:107-33 PMID: 9670777
  66. Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1.
    Br J Pharmacol. 1998 Dec;125(7):1437-44 PMID: 9884071
  67. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency.
    J Clin Invest. 1999 Jan;103(1):129-35 PMID: 9884342
  68. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury.
    Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2445-50 PMID: 10051662
  69. Carbon monoxide stimulates the apical 70-pS K+ channel of the rat thick ascending limb.
    J Clin Invest. 1999 Apr;103(7):963-70 PMID: 10194468
  70. Guanylate cyclase and the .NO/cGMP signaling pathway.
    Biochim Biophys Acta. 1999 May 5;1411(2-3):334-50 PMID: 10320667
  71. Interaction of heme oxygenase-2 with nitric oxide donors. Is the oxygenase an intracellular 'sink' for NO?
    Eur J Biochem. 1999 Sep;264(3):854-61 PMID: 10491133
  72. Heme oxygenase immunoreactive neurons in the rat intestine and their relationship to nitrergic neurons.
    J Auton Nerv Syst. 1999 Jul 7;77(1):4-12 PMID: 10494744
  73. Different mechanisms underlying the stimulation of K(Ca) channels by nitric oxide and carbon monoxide.
    J Clin Invest. 2002 Sep;110(5):691-700 PMID: 12208870
  74. Investigation of the potential modulatory effect of biliverdin, carbon monoxide and bilirubin on nitrergic neurotransmission in the pig gastric fundus.
    Eur J Pharmacol. 2002 Dec 20;457(2-3):177-86 PMID: 12464364
  75. NPAS2: a gas-responsive transcription factor.
    Science. 2002 Dec 20;298(5602):2385-7 PMID: 12446832
  76. RDP58, a locally active TNF inhibitor, is effective in the dextran sulphate mouse model of chronic colitis.
    Inflamm Res. 2002 Nov;51(11):522-31 PMID: 12540016
  77. Inhaled carbon monoxide suppresses the development of postoperative ileus in the murine small intestine.
    Gastroenterology. 2003 Feb;124(2):377-91 PMID: 12557144
  78. Endogenous carbon monoxide is an endothelial-derived vasodilator factor in the mesenteric circulation.
    Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H838-45 PMID: 12446283
  79. Immunocolocalization of the heme oxygenase-2 and interstitial cells of Cajal in normal and aganglionic colon.
    J Pediatr Surg. 2003 Jan;38(1):73-7 PMID: 12592623
  80. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite.
    Proc Natl Acad Sci U S A. 1989 Jan;86(1):99-103 PMID: 2911585
  81. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme.
    Proc Natl Acad Sci U S A. 1990 Jan;87(2):682-5 PMID: 1689048
  82. Is bilirubin good for you?
    Clin Perinatol. 1990 Jun;17(2):359-69 PMID: 2196134
  83. Carbon monoxide relaxes ileal smooth muscle through activation of guanylate cyclase.
    Biochem Pharmacol. 1991 Apr 15;41(8):1195-201 PMID: 1672594
  84. Induction of heme oxygenase in the small intestinal epithelium: a response to oral cadmium exposure.
    Toxicology. 1991 Apr 8;67(2):199-210 PMID: 2031253
  85. Does carbon monoxide have a physiological function?
    Trends Pharmacol Sci. 1991 May;12(5):185-8 PMID: 1862533
  86. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.
    J Clin Invest. 1992 Jul;90(1):267-70 PMID: 1634613
  87. NO., CO and .OH. Endogenous soluble guanylyl cyclase-activating factors.
    FEBS Lett. 1992 Jul 27;307(1):102-7 PMID: 1353461
  88. Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme.
    Circ Res. 1999 Oct 15;85(8):663-71 PMID: 10521239
  89. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema.
    Am J Hum Genet. 2000 Jan;66(1):187-95 PMID: 10631150
  90. Heme oxygenase-2 distribution in anorectum: colocalization with neuronal nitric oxide synthase.
    Am J Physiol Gastrointest Liver Physiol. 2000 Jan;278(1):G148-55 PMID: 10644573
  91. Carbon monoxide and nitric oxide as coneurotransmitters in the enteric nervous system: evidence from genomic deletion of biosynthetic enzymes.
    Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1851-5 PMID: 10677545
  92. Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS.
    Am J Physiol. 1999 Dec;277(6 Pt 2):F882-9 PMID: 10600935
  93. Heme oxygenase, carbon monoxide, and interstitial cells of Cajal.
    Microsc Res Tech. 1999 Dec 1;47(5):321-4 PMID: 10602291
  94. Distribution of heme oxygenase 2 in nerves and c-kit(+) interstitial cells in human stomach.
    Histochem Cell Biol. 1999 Oct;112(4):317-22 PMID: 10550617
  95. The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis.
    Free Radic Res. 1999 Dec;31(6):459-75 PMID: 10630670
  96. Heme oxygenase activity in the internal anal sphincter: effects of nonadrenergic, noncholinergic nerve stimulation.
    Gastroenterology. 2000 Mar;118(3):477-86 PMID: 10702198
  97. Influence of bilirubin and other antioxidants on nitrergic relaxation in the pig gastric fundus.
    Br J Pharmacol. 2000 Mar;129(6):1201-11 PMID: 10725269
  98. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway.
    Nat Med. 2000 Apr;6(4):422-8 PMID: 10742149
  99. Prevention of hypoxia-induced pulmonary hypertension by enhancement of endogenous heme oxygenase-1 in the rat.
    Circ Res. 2000 Jun 23;86(12):1224-9 PMID: 10864912
  100. Molecular mechanism of cGMP-mediated smooth muscle relaxation.
    J Cell Physiol. 2000 Sep;184(3):409-20 PMID: 10911373
Article Info
Journal
The Journal of physiology
Abbr.
J Physiol
ISSN
0022-3751
DOI
10.1113/jphysiol.2003.056556
Published
2004-04-15
Epub
2004-00-06
Pages
325-36
Language
English
Region
England
NLM ID
0266262
PMCID
PMC1664954
Subset
IM
Grants
NIDDK NIH HHS · DK 52766 · United States
NIDDK NIH HHS · R01 DK052766 · United States
NIDDK NIH HHS · R01 DK057061 · United States
NIDDK NIH HHS · DK 57061 · United States
NIDDK NIH HHS · DK 17238 · United States
NIDDK NIH HHS · R01 DK017238 · United States
External Links
PubMed source DOI: 10.1113/jphysiol.2003.056556 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2