Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The therapeutic potential of carbon monoxide

Nature Reviews Drug Discovery volume 9, pages 728–743 (2010)Cite this article

Subjects

Key Points

  • For more than a century, carbon monoxide (CO) has been primarily studied as a toxic substance that interferes with oxygen delivery to tissue beds. This dogma has changed in recent years, whereby low concentrations of CO displays remarkably protective effects against disease pathology.

  • CO is now being viewed as a protective homeostatic molecule that is being developed for therapy as an inhaled gas and as CO-releasing molecules (CO-RMs). This concept stemmed from the extensive studies of haem oxygenase, which is a cytoprotective enzyme that is thought to impart benefit through its ability to generate CO.

  • There is a large amount of broad preclinical evidence of the benefits of CO in large and small animal models. Importantly, CO is effective both as a prophylactic and as a therapeutic in diverse models, such as malaria, organ transplantation and pulmonary hypertension.

  • Inhaled CO and CO-RMs are in development as therapeutics; inhaled CO is being tested in Phase II clinical trials for kidney transplantation and various CO-RMs are under preclinical evaluation.

  • The precise molecular targets for CO remain unclear with a wide range of evidence for both haem and non-haem targets. A commonality revolves around the contributions of the mitochondria and alterations in cellular bioenergetics.

  • Inhaled CO delivery can be accomplished with an innovative delivery device. In addition strong medicinal chemistry is driving CO-RM development with efforts towards tissue specificity and the appropriate pharmacokinetic and pharmacodynamic profiling.

Abstract

Carbon monoxide (CO) is increasingly being accepted as a cytoprotective and homeostatic molecule with important signalling capabilities in physiological and pathophysiological situations. The endogenous production of CO occurs through the activity of constitutive (haem oxygenase 2) and inducible (haem oxygenase 1) haem oxygenases, enzymes that are responsible for the catabolism of haem. Through the generation of its products, which in addition to CO includes the bile pigments biliverdin, bilirubin and ferrous iron, the haem oxygenase 1 system also has an obligatory role in the regulation of the stress response and in cell adaptation to injury. This Review provides an overview of the physiology of CO, summarizes the effects of CO gas and CO-releasing molecules in preclinical animal models of cardiovascular disease, inflammatory disorders and organ transplantation, and discusses the development and therapeutic options for the exploitation of this simple gaseous molecule.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The haem degradation pathway.
Figure 2: Interactions between the three gas-generating systems.
Figure 3: Potential mechanisms of action of carbon monoxide (CO) delivered as a gas or as a CO-releasing molecule (CO-RM) in preclinical models.
Figure 4: Effects of inhaled carbon monoxide on Plasmodium berghei-induced blood–brain barrier disruption and parenchymal brain haemorrhage.
Figure 5: CO-RM2 rescues HO1-deficient mice from arterial thrombosis after aortic transplantation.
Figure 6: Inhaled carbon monoxide (CO) or CO-releasing molecule (CO-RM) administration enhances re-endothelialization after wire-trauma injury in mice.

Similar content being viewed by others

References

  1. Haldane, J. B. Carbon monoxide as a tissue poison. Biochem. J. 21, 1068–1075 (1927).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Douglas, C. G., Haldane, J. S. & Haldane, J. B. The laws of combination of haemoglobin with carbon monoxide and oxygen. J. Physiol. 44, 275–304 (1912).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Tenhunen, R., Marver, H. S. & Schmid, R. The enzymatic conversion of haem to bilirubin by microsomal haem oxygenase. Proc. Natl Acad. Sci. USA 61, 748–755 (1968).

    CAS  PubMed  Google Scholar 

  4. Boehning, D. & Snyder, S. H. Circadian rhythms. Carbon monoxide and clocks. Science 298, 2339–2340 (2002).

    CAS  PubMed  Google Scholar 

  5. Zhuo, M., Small, S. A., Kandel, E. R. & Hawkins, R. D. Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science 260, 1946–1949 (1993).

    CAS  PubMed  Google Scholar 

  6. Kobayashi, A. et al. Synergetic antioxidant and vasodilatory action of carbon monoxide in angiotensin II — induced cardiac hypertrophy. Hypertension 50, 1040–1048 (2007).

    CAS  PubMed  Google Scholar 

  7. Yachie, A. et al. Oxidative stress causes enhanced endothelial cell injury in human haem oxygenase-1 deficiency. J. Clin. Invest. 103, 129–135 (1999). This review describes the identification of the first human case of HO1 deficiency. It gives the clinical profile of a 6-year-old boy lacking the ability to generate CO and biliverdin.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Poss, K. D. & Tonegawa, S. Reduced stress defense in haem oxygenase 1-deficient cells. Proc. Natl Acad. Sci. USA 94, 10925–10930 (1997).

    CAS  PubMed  Google Scholar 

  9. Bloch, K. D., Ichinose, F., Roberts, J. D. Jr, & Zapol, W. M. Inhaled NO as a therapeutic agent. Cardiovasc. Res. 75, 339–348 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Szabo, C. Hydrogen sulphide and its therapeutic potential. Nature Rev. Drug Discov. 6, 917–935 (2007).

    CAS  Google Scholar 

  11. Boczkowski, J., Poderoso, J. J. & Motterlini, R. CO–metal interaction: vital signaling from a lethal gas. Trends Biochem. Sci. 31, 614–621 (2006). This review highlights the importance of CO–metal interaction in cell signalling and gives a comprehensive discussion on how the reactivity of CO with preferential metalloproteins can be translated into beneficial effects.

    CAS  PubMed  Google Scholar 

  12. Zuckerbraun, B. S. et al. Carbon monoxide protects against liver failure through nitric oxide-induced haem oxygenase 1. J. Exp. Med. 198, 1707–1716 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zuckerbraun, B. S. et al. Carbon monoxide reverses established pulmonary hypertension. J. Exp. Med. 203, 2109–2119 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bilban, M. et al. Haem oxygenase and carbon monoxide initiate homeostatic signaling. J. Mol. Med. 86, 267–279 (2008).

    CAS  PubMed  Google Scholar 

  15. Foresti, R., Bani-Hani, M. G. & Motterlini, R. Use of carbon monoxide as a therapeutic agent: promises and challenges. Intensive Care Med. 34, 649–658 (2008).

    CAS  PubMed  Google Scholar 

  16. Bauer, I. & Pannen, B. H. Bench-to-bedside review: carbon monoxide — from mitochondrial poisoning to therapeutic use. Crit. Care 13, 220 (2009).

    PubMed  PubMed Central  Google Scholar 

  17. Maines, M. D. The haem oxygenase system: a regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 37, 517–554 (1997).

    CAS  PubMed  Google Scholar 

  18. Ryter, S. W., Alam, J. & Choi, A. M. Haem oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol. Rev. 86, 583–650 (2006).

    CAS  PubMed  Google Scholar 

  19. Motterlini, R., Green, C. J. & Foresti, R. Regulation of haem oxygenase-1 by redox signals involving nitric oxide. Antioxid. Redox Signal. 4, 615–624 (2002).

    CAS  PubMed  Google Scholar 

  20. Otterbein, L. E., Soares, M. P., Yamashita, K. & Bach, F. H. Haem oxygenase-1: unleashing the protective properties of haem. Trends Immunol. 24, 449–455 (2003).

    CAS  PubMed  Google Scholar 

  21. Stocker, R. Antioxidant activities of bile pigments. Antioxid. Redox. Signal. 6, 841–849 (2004).

    CAS  PubMed  Google Scholar 

  22. Ollinger, R. et al. Bilirubin and biliverdin treatment of atherosclerotic diseases. Cell Cycle 6, 39–43 (2007).

    PubMed  Google Scholar 

  23. Ollinger, R. et al. Therapeutic applications of bilirubin and biliverdin in transplantation. Antioxid. Redox Signal. 9, 2175–2185 (2007).

    PubMed  Google Scholar 

  24. Yamada, N. et al. Microsatellite polymorphism in the haem oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am. J. Hum. Genet. 66, 187–195 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wagener, F. A. et al. HMOX1 promoter polymorphism modulates the relationship between disease activity and joint damage in rheumatoid arthritis. Arthritis Rheum. 58, 3388–3393 (2008).

    CAS  PubMed  Google Scholar 

  26. Song, F. et al. Association between haem oxygenase-1 gene promoter polymorphisms and type 2 diabetes in a Chinese population. Am. J. Epidemiol. 170, 747–756 (2009).

    PubMed  Google Scholar 

  27. Brydun, A. et al. Reduced expression of haem oxygenase-1 in patients with coronary atherosclerosis. Hypertens. Res. 30, 341–348 (2007).

    CAS  PubMed  Google Scholar 

  28. Nath, K. A. et al. Induction of haem oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J. Clin. Invest. 90, 267–270 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Belcher, J. D. et al. Haem oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. J. Clin. Invest. 116, 808–816 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Otterbein, L. E. et al. Exogenous administration of haem oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J. Clin. Invest. 103, 1047–1054 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Tzima, S., Victoratos, P., Kranidioti, K., Alexiou, M. & Kollias, G. Myeloid haem oxygenase-1 regulates innate immunity and autoimmunity by modulating IFN-β production. J. Exp. Med. 206, 1167–1179 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. D'Amico, G., Lam, F., Hagen, T. & Moncada, S. Inhibition of cellular respiration by endogenously produced carbon monoxide. J. Cell Sci. 119, 2291–2298 (2006).

    CAS  PubMed  Google Scholar 

  33. Dioum, E. M. et al. NPAS2: a gas-responsive transcription factor. Science 298, 2385–2387 (2002).

    CAS  PubMed  Google Scholar 

  34. Otterbein, L. E. et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nature Med. 6, 422–428 (2000).

    CAS  PubMed  Google Scholar 

  35. Zhang, X., Shan, P., Alam, J., Fu, X. Y. & Lee, P. J. Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a PI3K/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. J. Biol. Chem. 280, 8714–8721 (2004).

    PubMed  Google Scholar 

  36. Rodriguez, A. I. et al. HO-1 and CO decrease platelet-derived growth factor-induced vascular smooth muscle cell migration via inhibition of Nox1. Arterioscler. Thromb. Vasc. Biol. 30, 98–104 (2010).

    CAS  PubMed  Google Scholar 

  37. Zuckerbraun, B. S. et al. Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 21, 1099–1106 (2007).

    CAS  Google Scholar 

  38. Chin, B. Y. et al. Hypoxia-inducible factor 1α stabilization by carbon monoxide results in cytoprotective preconditioning. Proc. Natl Acad. Sci. USA 104, 5109–5114 (2007).

    CAS  Google Scholar 

  39. Desmard, M., Boczkowski, J., Poderoso, J. & Motterlini, R. Mitochondrial and cellular haem-dependent proteins as targets for the bioactive function of the haem oxygenase/carbon monoxide system. Antioxid. Redox Signal. 9, 2139–2155 (2007).

    CAS  PubMed  Google Scholar 

  40. Furchgott, R. F. & Jothianandan, D. Endothelium-dependent and -independent vasodilation involving cGMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels 28, 52–61 (1991).

    CAS  PubMed  Google Scholar 

  41. Abraham, N. G. & Kappas, A. Pharmacological and clinical aspects of haem oxygenase. Pharmacol. Rev. 60, 79–127 (2008).

    CAS  PubMed  Google Scholar 

  42. Sarady, J. K. et al. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J. 18, 854–856 (2004).

    PubMed  Google Scholar 

  43. Wegiel, B. et al. Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury. Circulation 121, 537–548 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hartsfield, C. L. et al. Cardioprotective and vasomotor effects of HO activity during acute and chronic hypoxia. Am. J. Physiol. Heart Circ. Physiol. 287, H2009–H2015 (2004).

    CAS  PubMed  Google Scholar 

  45. Motterlini, R. et al. Haem oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ. Res. 83, 568–577 (1998).

    CAS  PubMed  Google Scholar 

  46. Motterlini, R. et al. Bioactivity and pharmacological actions of carbon monoxide-releasing molecules. Curr. Pharmacol. Design 9, 2525–2539 (2003).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. Hou, S., Heinemann, S. H. & Hoshi, T. Modulation of BKCa channel gating by endogenous signaling molecules. Physiology (Bethesda) 24, 26–35 (2009).

    CAS  Google Scholar 

  49. Pogson, Z. E. et al. Exhaled carbon monoxide in asthmatic adults with bronchial reactivity: a prospective study. J. Asthma 46, 665–669 (2009).

    CAS  PubMed  Google Scholar 

  50. Sylvester, K. P. et al. Exhaled carbon monoxide levels in children with sickle cell disease. Eur. J. Pediatr. 164, 162–165 (2005).

    CAS  PubMed  Google Scholar 

  51. Paredi, P., Biernacki, W., Invernizzi, G., Kharitonov, S. A. & Barnes, P. J. Exhaled carbon monoxide levels elevated in diabetes and correlated with glucose concentration in blood. A new test for monitoring the disease? Chest 116, 1007–1011 (1999).

    CAS  PubMed  Google Scholar 

  52. Bigler, R. E. & Sgouros, G. Biological analysis and dosimetry for 15O-labeled O2, CO2, and CO gases administered continuously by inhalation. J. Nucl. Med. 24, 431–437 (1983).

    CAS  PubMed  Google Scholar 

  53. Dercho, R. A., Nakatsu, K., Wong, R. J., Stevenson, D. K. & Vreman, H. J. Determination of in vivo carbon monoxide production in laboratory animals via exhaled air. J. Pharmacol. Toxicol. Methods 54, 288–295 (2006).

    CAS  PubMed  Google Scholar 

  54. Herrmann, W. A. 100 years of metal carbonyls. A serendipitous chemical discovery of major scientific and industrial impact. J. Organomet. Chem. 383, 21–44 (1990).

    Google Scholar 

  55. Motterlini, R. et al. Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ. Res. 90, E17–E24 (2002). This is the first publication reporting the identification, characterization and pharmacological effects of transition metal carbonyls as CO-RMs.

    CAS  PubMed  Google Scholar 

  56. Clark, J. E. et al. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ. Res. 93, e2–e8 (2003).

    CAS  PubMed  Google Scholar 

  57. Motterlini, R. et al. CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule. FASEB J. 19, 284–286 (2005).

    CAS  PubMed  Google Scholar 

  58. Foresti, R. et al. Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule. Br. J. Pharmacol. 142, 453–460 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Koneru, P. & Leffler, C. W. Role of cGMP in carbon monoxide-induced cerebral vasodilation in piglets. Am. J. Physiol. Heart Circ. Physiol. 286, H304–H309 (2004).

    CAS  PubMed  Google Scholar 

  60. Arregui, B. et al. Acute renal hemodynamic effects of dimanganese decacarbonyl and cobalt protoporphyrin. Kidney Int. 65, 564–574 (2004).

    CAS  PubMed  Google Scholar 

  61. Ryan, M. J. et al. Renal vascular responses to CORM-A1 in the mouse. Pharmacol. Res. 54, 24–29 (2006).

    CAS  PubMed  Google Scholar 

  62. Botros, F. T. & Navar, L. G. Interaction between endogenously-produced carbon monoxide and nitric oxide in regulation of renal afferent arterioles. Am. J. Physiol. Heart Circ. Physiol. 291, H2772–H2778 (2006).

    CAS  PubMed  Google Scholar 

  63. Van Landeghem, L. et al. Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver. Liver Int. 29, 650–660 (2009).

    CAS  PubMed  Google Scholar 

  64. Bolognesi, M. et al. Carbon monoxide-mediated activation of large-conductance calcium-activated potassium channels contributes to mesenteric vasodilatation in cirrhotic rats. J. Pharmacol. Exp. Ther. 321, 187–194 (2007).

    CAS  PubMed  Google Scholar 

  65. Sawle, P. et al. Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br. J. Pharmacol. 145, 800–810 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bani-Hani, M. G., Greenstein, D., Mann, B. E., Green, C. J. & Motterlini, R. Modulation of thrombin-induced neuroinflammation in BV-2 microglia by a carbon monoxide-releasing molecule (CORM-3). J. Pharmacol. Exp. Ther. 318, 1315–1322 (2006).

    CAS  PubMed  Google Scholar 

  67. Tsoyi, K. et al. Activation of PPAR-γ by carbon monoxide from CORM-2 leads to the inhibition of iNOS but not COX-2 expression in LPS-stimulated macrophages. Inflammation 32, 364–371 (2009).

    CAS  PubMed  Google Scholar 

  68. Brouard, S. et al. Carbon monoxide generated by haem oxygenase 1 suppresses endothelial cell apoptosis. J. Exp. Med. 192, 1015–1026 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Kim, K. M. et al. Carbon monoxide induces haem oxygenase-1 via activation of protein kinase R-like endoplasmic reticulum kinase and inhibits endothelial cell apoptosis triggered by endoplasmic reticulum stress. Circ. Res. 101, 919–927 (2007).

    CAS  PubMed  Google Scholar 

  70. Kim, H. S., Loughran, P. A., Rao, J., Billiar, T. R. & Zuckerbraun, B. S. Carbon monoxide activates NF-κB via ROS generation and Akt pathways to protect against cell death of hepatocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G146–G152 (2008).

    CAS  PubMed  Google Scholar 

  71. Choi, B. M., Pae, H. O., Kim, Y. M. & Chung, H. T. Nitric oxide-mediated cytoprotection of hepatocytes from glucose deprivation-induced cytotoxicity: involvement of haem oxygenase-1. Hepatology 37, 810–823 (2003).

    CAS  PubMed  Google Scholar 

  72. Zheng, L. et al. Carbon monoxide modulates α-smooth muscle actin and small proline rich-1a expression in fibrosis. Am. J. Respir. Cell. Mol. Biol. 41, 85–92 (2009).

    CAS  PubMed  Google Scholar 

  73. Zhou, Z. et al. Carbon monoxide suppresses bleomycin-induced lung fibrosis. Am. J. Pathol. 166, 27–37 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. McDaid, J. et al. Haem oxygenase-1 modulates the allo-immune response by promoting activation-induced cell death of T cells. FASEB J. 19, 458–460 (2005).

    CAS  PubMed  Google Scholar 

  75. Song, R. et al. Carbon monoxide promotes Fas/CD95-induced apoptosis in Jurkat cells. J. Biol. Chem. 279, 44327–44334 (2004).

    CAS  PubMed  Google Scholar 

  76. Hu, C. M., Lin, H. H., Chiang, M. T., Chang, P. F. & Chau, L. Y. Systemic expression of haem oxygenase-1 ameliorates type 1 diabetes in NOD mice. Diabetes 56, 1240–1247 (2007).

    CAS  PubMed  Google Scholar 

  77. Lee, S. S. et al. Haem oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J. 21, 3450–3457 (2007).

    CAS  PubMed  Google Scholar 

  78. Suliman, H. B. et al. The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J. Clin. Invest. 117, 3730–3741 (2007). This article shows a direct role of HO-derived CO in reversing doxorubicin-induced cardiomyopathy through mechanisms that involve mitochondrial biogenesis and mitigation of apoptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bilban, M. et al. Carbon monoxide orchestrates a protective response through PPARγ. Immunity 24, 601–610 (2006).

    CAS  PubMed  Google Scholar 

  80. Suliman, H. B., Carraway, M. S., Tatro, L. G. & Piantadosi, C. A. A new activating role for CO in cardiac mitochondrial biogenesis. J. Cell Sci. 120, 299–308 (2006).

    PubMed  Google Scholar 

  81. Pamplona, A. et al. Haem oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nature Med. 13, 703–710 (2007).

    CAS  PubMed  Google Scholar 

  82. Freitas, A. et al. Haem oxygenase/carbon monoxide-biliverdin pathway down regulates neutrophil rolling, adhesion and migration in acute inflammation. Br. J. Pharmacol. 149, 345–354 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Cepinskas, G., Katada, K., Bihari, A. & Potter, R. F. Carbon monoxide liberated from carbon monoxide-releasing molecule CORM-2 attenuates inflammation in the liver of septic mice. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G184–G191 (2008).

    CAS  PubMed  Google Scholar 

  84. Mizuguchi, S. et al. CO-releasing molecule (CORM-3)-derived CO modulates neutrophil (PMN) migration across vascular endothelium by reducing the levels of cell surface-bound elastase. Am. J. Physiol. Heart Circ. Physiol. 297, H920–H929 (2009).

    CAS  PubMed  Google Scholar 

  85. Tsoyi, K. et al. Haem-oxygenase-1 induction and carbon monoxide-releasing molecule inhibit lipopolysaccharide (LPS)-induced high-mobility group Box 1 release in vitro and improve survival of mice in LPS- and cecal ligation and puncture-induced sepsis model in vivo. Mol. Pharmacol. 76, 173–182 (2009).

    CAS  PubMed  Google Scholar 

  86. Lancel, S. et al. Carbon monoxide rescues mice from lethal sepsis by supporting mitochondrial energetic metabolism and activating mitochondrial biogenesis. J. Pharmacol. Exp. Ther. 1329, 641–648 (2009). This study reports on the effect of a water-soluble CO-RM (CO-RM-3) in rescuing mice from lethal sepsis, implicating mitochondrial biogenesis and bioenergetics as major determinants of the observed protection.

    Google Scholar 

  87. Ferrandiz, M. L. et al. Treatment with a CO-releasing molecule (CORM-3) reduces joint inflammation and erosion in murine collagen-induced arthritis. Ann. Rheum. Dis. 67, 1211–1217 (2008).

    CAS  PubMed  Google Scholar 

  88. Napolitano, L. M. Carbon monoxide and ileus: inhaled gas to prevent retained gas? Crit. Care Med. 33, 1445–1446 (2005).

    PubMed  Google Scholar 

  89. Nakao, A. et al. A single intraperitoneal dose of carbon monoxide-saturated ringer's lactate solution ameliorates postoperative ileus in mice. J. Pharmacol. Exp. Ther. 319, 1265–1275 (2006).

    CAS  PubMed  Google Scholar 

  90. De Backer, O. et al. Water-soluble CO-releasing molecules (CO-RMs) reduce the development of postoperative ileus via modulation of MAPK/HO-1 signaling and reduction of oxidative stress. Gut 58, 347–356 (2009).

    CAS  PubMed  Google Scholar 

  91. Masini, E. et al. A carbon monoxide-releasing molecule (CORM-3) abrogates polymorphonuclear granulocyte-induced activation of endothelial cells and mast cells. FASEB J. 22, 3380–3388 (2008).

    CAS  PubMed  Google Scholar 

  92. Seldon, M. P. et al. Haem oxygenase-1 inhibits the expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-κB RelA phosphorylation at serine 276. J. Immunol. 179, 7840–7851 (2007).

    CAS  PubMed  Google Scholar 

  93. Chora, A. A. et al. Haem oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation. J. Clin. Invest. 117, 438–447 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Beckman, J. D. et al. Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease. Am. J. Physiol. Heart Circ. Physiol. 297, H1243–H1253 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Bains, S. K. et al. Human sickle cell blood modulates endothelial haem oxygenase activity. Effects on vascular adhesion and reactivity. Arterioscler. Thromb. Vasc. Biol. 30, 305–312 (2010).

    CAS  PubMed  Google Scholar 

  96. Nicolai, A. et al. Haem oxygenase-1 induction remodels adipose tissue and improves insulin sensitivity in obesity-induced diabetic rats. Hypertension 53, 508–515 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Di Pascoli, M. et al. Chronic CO levels has a beneficial effect on vascular relaxation in diabetes. Biochem. Biophys. Res. Commun. 340, 935–943 (2006).

    CAS  PubMed  Google Scholar 

  98. Sass, G. et al. Haem oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice. Hepatology 38, 909–918 (2003).

    CAS  PubMed  Google Scholar 

  99. Hegazi, R. A. et al. Carbon monoxide ameliorates chronic murine colitis through a haem oxygenase 1-dependent pathway. J. Exp. Med. 202, 1703–1713 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Chung, S. W., Liu, X., Macias, A. A., Baron, R. M. & Perrella, M. A. Haem oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice. J. Clin. Invest. 118, 239–247 (2008).

    CAS  PubMed  Google Scholar 

  101. Desmard, M. et al. A carbon monoxide-releasing molecule (CORM-3) exerts bactericidal activity against Pseudomonas aeruginosa and improves survival in an animal model of bacteraemia. FASEB J. 23, 1023–1031 (2009). The first study to report on the potential bactericidal effects of a water-soluble CO-RM (CO-RM-3) in an in vivo model of bacteraemia.

    CAS  PubMed  Google Scholar 

  102. Chen, B. et al. Carbon monoxide rescues haem oxygenase-1-deficient mice from arterial thrombosis in allogeneic aortic transplantation. Am. J. Pathol. 175, 422–429 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Brune, B. & Ullrich, V. Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol. Pharmacol. 32, 497–504 (1987).

    CAS  PubMed  Google Scholar 

  104. Chlopicki, S., Olszanecki, R., Marcinkiewicz, E., Lomnicka, M. & Motterlini, R. Carbon monoxide released by CORM-3 inhibits human platelets by a mechanism independent of soluble guanylate cyclase. Cardiovasc. Res. 71, 393–401 (2006).

    CAS  PubMed  Google Scholar 

  105. Guo, Y. et al. Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo. Am. J. Physiol. Heart Circ. Physiol. 286, H1649–H1653 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Varadi, J. et al. Beneficial effects of carbon monoxide-releasing molecules on post-ischemic myocardial recovery. Life Sci. 80, 1619–1626 (2007).

    CAS  PubMed  Google Scholar 

  107. Tang, X. D. et al. Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425, 531–535 (2003).

    CAS  PubMed  Google Scholar 

  108. Hou, S., Xu, R., Heinemann, S. H. & Hoshi, T. The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels. Proc. Natl Acad. Sci. USA 105, 4039–4043 (2008).

    CAS  PubMed  Google Scholar 

  109. Otterbein, L. E. et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nature Med. 9, 183–190 (2003).

    CAS  PubMed  Google Scholar 

  110. Raman, K. G. et al. Inhaled carbon monoxide inhibits intimal hyperplasia and provides added benefit with nitric oxide. J. Vasc. Surg. 44, 151–158 (2006).

    PubMed  Google Scholar 

  111. Ramlawi, B. et al. Inhaled carbon monoxide prevents graft-induced intimal hyperplasia in swine. J. Surg. Res. 138, 121–127 (2007).

    CAS  PubMed  Google Scholar 

  112. Stone, G. W. et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N. Engl. J. Med. 356, 998–1008 (2007).

    CAS  PubMed  Google Scholar 

  113. Ma, X. et al. Delayed re-endothelialization with rapamycin-coated stents is rescued by the addition of a glycogen synthase kinase-3β inhibitor. Cardiovasc. Res. 86, 338–345 (2010).

    CAS  PubMed  Google Scholar 

  114. Akamatsu, Y. et al. Haem oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J. 18, 771–772 (2004).

    CAS  PubMed  Google Scholar 

  115. Sato, K. et al. Carbon monoxide generated by haem oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. J. Immunol. 166, 4185–4194 (2001).

    CAS  PubMed  Google Scholar 

  116. Bagul, A., Hosgood, S. A., Kaushik, M. & Nicholson, M. L. Carbon monoxide protects against ischemia-reperfusion injury in an experimental model of controlled nonheartbeating donor kidney. Transplantation 85, 576–581 (2008).

    CAS  PubMed  Google Scholar 

  117. Nakao, A., Choi, A. M. & Murase, N. Protective effect of carbon monoxide in transplantation. J. Cell. Mol. Med. 10, 650–671 (2006).

    CAS  PubMed  Google Scholar 

  118. Sandouka, A. et al. Treatment with carbon monoxide-releasing molecules (CO-RMs) during cold storage improves renal function at reperfusion. Kidney Int. 69, 239–247 (2006).

    CAS  PubMed  Google Scholar 

  119. Musameh, M. D., Green, C. J., Mann, B. E., Fuller, B. J. & Motterlini, R. Improved myocardial function after cold storage with preservation solution supplemented with a carbon monoxide-releasing molecule (CORM-3). J. Heart Lung Transplant 26, 1192–1198 (2007).

    PubMed  Google Scholar 

  120. Pizarro, M. D. et al. Protective effects of a carbon monoxide-releasing molecule (CORM-3) during hepatic cold preservation. Cryobiology 58, 248–255 (2009).

    CAS  PubMed  Google Scholar 

  121. Nakao, A. et al. Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am. J. Pathol. 163, 1587–1598 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Nakao, A. et al. Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am. J. Transplant. 6, 2243–2255 (2006).

    CAS  PubMed  Google Scholar 

  123. Neto, J. S. et al. Protection of transplant-induced renal ischemia/reperfusion injury with carbon monoxide. Am. J. Physiol. Renal Physiol. 287, F979–F989 (2004).

    PubMed  Google Scholar 

  124. Stec, D. E. et al. Carbon monoxide (CO) protects renal tubular epithelial cells against cold-rewarm apoptosis. Ren. Fail. 29, 543–548 (2007).

    CAS  PubMed  Google Scholar 

  125. Nakao, A. et al. Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts. Kidney Int. 74, 1009–1016 (2008).

    CAS  PubMed  Google Scholar 

  126. Yoshida, J. et al. Ex vivo application of carbon monoxide in UW solution prevents transplant-induced renal ischemia/reperfusion injury in pigs. Am. J. Transplant. 10, 763–772 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Motterlini, R., Mann, B. E. & Foresti, R. Therapeutic applications of carbon monoxide-releasing molecules (CO-RMs). Expert Opin. Investig. Drugs 14, 1305–1318 (2005).

    CAS  PubMed  Google Scholar 

  128. Bannenberg, G. L. & Vieira, H. L. Therapeutic applications of the gaseous mediators carbon monoxide and hydrogen sulfide. Expert. Opin. Ther. Pat. 19, 663–682 (2009).

    CAS  PubMed  Google Scholar 

  129. Alberto, R. & Motterlini, R. Chemistry and biological activities of CO-releasing molecules (CORMs) and transition metal complexes. Dalton Trans. 1651–1660 (2007).

  130. Piantadosi, C. A. Carbon monoxide, reactive oxygen signaling, and oxidative stress. Free Radic. Biol. Med. 45, 562–569 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Piantadosi, C. A. Biological chemistry of carbon monoxide. Antioxid. Redox Signal. 4, 259–270 (2002).

    CAS  PubMed  Google Scholar 

  132. Taille, C., El-Benna, J., Lanone, S., Boczkowski, J. & Motterlini, R. Mitochondrial respiratory chain and NAD(P)H oxidase are targets for the antiproliferative effect of carbon monoxide in human airway smooth muscle. J. Biol. Chem. 280, 25350–25360 (2005).

    CAS  PubMed  Google Scholar 

  133. Inverardi, L. et al. Early recognition of a discordant xenogeneic organ by human circulating lymphocytes. J. Immunol. 149, 1416–1423 (1992).

    CAS  PubMed  Google Scholar 

  134. Lavitrano, M. et al. Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs. FASEB J. 18, 1093–1095 (2004).

    CAS  PubMed  Google Scholar 

  135. Tsui, T. Y. et al. Carbon monoxide inhalation rescues mice from fulminant hepatitis through improving hepatic energy metabolism. Shock 27, 165–171 (2007).

    CAS  PubMed  Google Scholar 

  136. Haab, P. The effect of carbon monoxide on respiration. Experientia 46, 1202–1206 (1990).

    CAS  PubMed  Google Scholar 

  137. Kapetanaki, S. M. et al. Interaction of carbon monoxide with the apoptosis-inducing cytochrome c-cardiolipin complex. Biochemistry 48, 1613–1619 (2009).

    CAS  PubMed  Google Scholar 

  138. Piantadosi, C. A., Carraway, M. S., Babiker, A. & Suliman, H. B. Haem oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ. Res. 103, 1232–1240 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Kim, H. P. & Choi, A. M. A new road to induce haem oxygenase-1 expression by carbon monoxide. Circ. Res. 101, 862–864 (2007).

    CAS  PubMed  Google Scholar 

  140. Nakao, A. et al. Heart allograft protection with low-dose carbon monoxide inhalation: effects on inflammatory mediators and alloreactive T-cell responses. Transplantation 81, 220–230 (2006).

    PubMed  Google Scholar 

  141. Kohmoto, J. et al. Carbon monoxide-saturated preservation solution protects lung grafts from ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg. 136, 1067–1075 (2008).

    PubMed  PubMed Central  Google Scholar 

  142. Minamoto, K., Harada, H., Lama, V. N., Fedarau, M. A. & Pinsky, D. J. Reciprocal regulation of airway rejection by the inducible gas-forming enzymes haem oxygenase and nitric oxide synthase. J. Exp. Med. 202, 283–294 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Mishra, S. et al. Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. Proc. Natl Acad. Sci. USA 103, 5191–5196 (2006).

    CAS  PubMed  Google Scholar 

  144. Zhang, X. et al. Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38α mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. J. Biol. Chem. 278, 22061–22070 (2003).

    CAS  PubMed  Google Scholar 

  145. Fujita, T. et al. Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis. Nature Med. 7, 598–604 (2001).

    CAS  PubMed  Google Scholar 

  146. Mak, I. T., Kramer, J. H., Freedman, A. M., Tse, S. Y. H. & Weglicki, W. B. Oxygen radical-mediated injury of myocytes-protection by propanolol. J. Mol. Cell. Cardiol. 22, 687–695 (1990).

    CAS  PubMed  Google Scholar 

  147. Ikeda, A. et al. Liver graft exposure to carbon monoxide during cold storage protects sinusoidal endothelial cells and ameliorates reperfusion injury in rats. Liver Transpl. 15, 1458–1468 (2009).

    PubMed  PubMed Central  Google Scholar 

  148. Kaizu, T. et al. Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G236–G244 (2008).

    CAS  PubMed  Google Scholar 

  149. Neto, J. S. et al. Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. Am. J. Physiol. Renal Physiol. 290, F324–F334 (2006).

    PubMed  Google Scholar 

  150. Nakao, A. et al. Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function. Am. J. Physiol. Renal Physiol. 297, F19–F26 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Ott, M. C. et al. Inhalation of carbon monoxide prevents liver injury and inflammation following hind limb ischemia/reperfusion. FASEB J. 19, 106–108 (2005).

    CAS  PubMed  Google Scholar 

  152. Amersi, F. et al. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology 35, 815–823 (2002).

    CAS  PubMed  Google Scholar 

  153. Nakao, A. et al. Immunomodulatory effects of inhaled carbon monoxide on rat syngeneic small bowel graft motility. Gut 52, 1278–1285 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Nakao, A. et al. Protective effect of carbon monoxide inhalation for cold-preserved small intestinal grafts. Surgery 134, 285–292 (2003).

    PubMed  Google Scholar 

  155. Wang, H. et al. Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes 54, 1400–1406 (2005).

    CAS  PubMed  Google Scholar 

  156. Takamiya, R. et al. High mobility group Box 1 contributes to lethality of endotoxemia in haem oxygenase-1 deficient mice. Am. J. Respir. Cell. Mol. Biol. 41, 129–135 (2008).

    PubMed  PubMed Central  Google Scholar 

  157. Mazzola, S. et al. Carbon monoxide pretreatment prevents respiratory derangement and ameliorates hyperacute endotoxic shock in pigs. FASEB J. 19, 2045–2047 (2005).

    CAS  PubMed  Google Scholar 

  158. Zuckerbraun, B. S. et al. Carbon monoxide prevents multiple organ injury in a model of hemorrhagic shock and resuscitation. Shock 23, 527–532 (2005).

    CAS  PubMed  Google Scholar 

  159. Cabrales, P., Tsai, A. G. & Intaglietta, M. Hemorrhagic shock resuscitation with carbon monoxide saturated blood. Resuscitation 72, 306–318 (2007).

    PubMed  Google Scholar 

  160. Urquhart, P., Rosignoli, G., Cooper, D., Motterlini, R. & Perretti, M. Carbon monoxide-releasing molecules modulate leukocyte-endothelial interactions under flow. J. Pharmacol. Exp. Ther. 321, 656–662 (2007).

    CAS  PubMed  Google Scholar 

  161. Otterbein, L. E., Mantell, L. L. & Choi, A. M. Carbon monoxide provides protection against hyperoxic lung injury. Am. J. Physiol. 276, L688–L694 (1999).

    CAS  PubMed  Google Scholar 

  162. Otterbein, L. E. et al. MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury. Am. J. Pathol. 163, 2555–2563 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Moore, B. A., Otterbein, L. E., Turler, A., Choi, A. M. & Bauer, A. J. Inhaled carbon monoxide suppresses the development of postoperative ileus in the murine small intestine. Gastroenterology 124, 377–391 (2003).

    CAS  PubMed  Google Scholar 

  164. Moore, B. A. et al. Brief inhalation of low-dose carbon monoxide protects rodents and swine from postoperative ileus. Crit. Care Med. 33, 1317–1326 (2005).

    CAS  PubMed  Google Scholar 

  165. Wang, L. et al. Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction. Am. J. Physiol. Renal Physiol. 294, F508–F517 (2008).

    CAS  PubMed  Google Scholar 

  166. Dubuis, E., Potier, M., Wang, R. & Vandier, C. Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCa channels. Cardiovasc. Res. 65, 751–761 (2005).

    CAS  PubMed  Google Scholar 

  167. Fujimoto, H. et al. Carbon monoxide protects against cardiac ischemia-reperfusion injury in vivo via MAPK and Akt-eNOS pathways. Arterioscler. Thromb. Vasc. Biol. 24, 1848–1853 (2004).

    CAS  PubMed  Google Scholar 

  168. Tayem, Y., Johnson, T. R., Mann, B. E., Green, C. J. & Motterlini, R. Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule. Am. J. Physiol. Renal Physiol. 290, F789–F794 (2006).

    CAS  PubMed  Google Scholar 

  169. Ren, Y. et al. Haem oxygenase metabolites inhibit tubuloglomerular feedback (TGF). Am. J. Physiol. Renal Physiol. 295, F1207–F1212 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Stagni, E. et al. A water-soluble carbon monoxide-releasing molecule (CORM-3) lowers intraocular pressure in rabbits. Br. J. Ophthalmol. 93, 254–257 (2009).

    CAS  PubMed  Google Scholar 

  171. Zimmermann, A., Leffler, C. W., Tcheranova, D., Fedinec, A. L. & Parfenova, H. Cerebroprotective effects of the CO-releasing molecule, CORM-A1, against seizure-induced neonatal vascular injury. Am. J. Physiol. Heart Circ. Physiol. 293, H2501–H2507 (2007).

    CAS  PubMed  Google Scholar 

  172. Allanson, M. & Reeve, V. E. Carbon monoxide signalling reduces photocarcinogenesis in the hairless mouse. Cancer Immunol. Immunother. 56, 1807–1815 (2007).

    CAS  PubMed  Google Scholar 

  173. Sun, B. W., Sun, Y., Sun, Z. W. & Chen, X. CO liberated from CORM-2 modulates the inflammatory response in the liver of thermally injured mice. World J. Gastroenterol. 14, 547–553 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Sun, B. et al. Role of CO-releasing molecules liberated CO in attenuating leukocytes sequestration and inflammatory responses in the lung of thermally injured mice. J. Surg. Res. 139, 128–135 (2007).

    CAS  PubMed  Google Scholar 

  175. Zuckerbraun, B. S. et al. Carbon monoxide protects against the development of experimental necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G607–G613 (2005).

    CAS  PubMed  Google Scholar 

  176. Ameredes, B. T. et al. Low-dose carbon monoxide reduces airway hyperresponsiveness in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L1270–L1276 (2003).

    CAS  PubMed  Google Scholar 

  177. Sun, B. W. et al. Carbon liberated from CO-releasing molecules attenuates leukocyte infiltration in the small intestine of thermally injured mice. World J. Gastroenterol. 13, 6183–6190 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Goebel, U. et al. Carbon monoxide inhalation reduces pulmonary inflammatory response during cardiopulmonary bypass in pigs. Anesthesiology 108, 1025–1036 (2008).

    CAS  PubMed  Google Scholar 

  179. Nobre, L. S., Seixas, J. D., Romao, C. C. & Saraiva, L. M. Antimicrobial action of carbon monoxide-releasing compounds. Antimicrob. Agents Chemother. 51, 4303–4307 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Penney, D. G. Carbon Monoxide 2–25 (CRC Press, New York, 1996).

    Google Scholar 

Download references

Acknowledgements

We thank W. Blättler and C. Romão for their constructive and helpful discussions on the manuscript and the medicinal chemistry. We also thank A. Berssenbrugge and F. Montgomery from Ikaria for their help with the Covox DS device information. L.E.O. is supported by the National Institutes of Health (5R01GM088666) and by the US Department of Defense Centre for Integration of Medicine and Innovative Technology. We thank the Julie Henry Fund of the Transplant Institute at the Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA, for their continued support.

Author information

Authors and Affiliations

  1. Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, Genoa, Italy

    Roberto Motterlini

  2. Department of Surgery, Room 603, Transplant Institute, Beth Israel Deaconess Medical Center, Center for Life Sciences 3 Blackfan Circle, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Leo E. Otterbein

Authors
  1. Roberto Motterlini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leo E. Otterbein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leo E. Otterbein.

Ethics declarations

Competing interests

Leo E. Otterbein and Roberto Motterlini are scientific consultants for Alfama Inc, Cambridge, Massachusetts, USA.

Related links

Related links

FURTHER INFORMATION

Otterbein laboratory homepage

Motterlini laboratory homepage

Glossary

Haem oxygenase

(HO). The enzyme responsible for the rate-limiting step in the degradation of haem to carbon monoxide and biliverdin. It is ubiquitously present in mammalian cells and exists in constitutive (HO2) and inducible and redox-sensitive (HO1) isoforms.

Haem

A prosthetic group of various proteins consisting of a large heterocyclic organic ring called porphyrin and a central metal atom (for example, iron, copper or zinc), which serves as a gas-sensor and a redox-sensor moiety.

(GT)n microsatellite polymorphism

A short tandem repeat DNA loci used as genetic markers. Such repeats can vary in their nucleotide sequence (polymorphic) leading to genetic variation and changes in the phenotype of a gene or of the cell.

Guanylyl cyclase

(GC). A haem-containing enzyme that catalyses the conversion of GTP to the second messenger 3′,5′-cyclic GMP and pyrophosphate. The soluble isoform (sGC) is a known receptor for both nitric oxide and carbon monoxide and is most notably involved in vasodilation.

NO synthase

(NOS). The enzyme system that generates nitric oxide, which acts as a neurotransmitter, a mediator of inflammation and a key regulator of vasomotor tone. There are three known isoforms of NOS: NOS I (neuronal NOS or nNOS), NOS II (inducible NOS or iNOS) and NOS III (endothelial NOS or eNOS).

NADPH oxidase

A membrane-bound and haem-dependent enzyme complex expressed, among other cells, primarily in phagocytes. It transfers electrons from NADPH to molecular oxygen to produce the superoxide anion, a reactive free radical.

Cytochrome c oxidase

Also known as complex IV, it is the last acceptor of electrons in the mitochondrial respiratory chain to reduce oxygen to water. Cyanide, carbon monoxide, nitric oxide and hydrogen sulphide can all compete with oxygen for the binding to cytochrome c oxidase, thus potentially inhibiting cellular respiration.

Reactive oxygen species

(ROS). Intermediates formed by the incomplete one-electron reduction of molecular oxygen and include singlet oxygen, superoxides, peroxides and hydroxyl radicals. They have crucial roles in oxidative stress, signal transduction, regulation of gene expression and host defence.

Carboxyhaemoglobin

(COHb). A stable complex of carbon monoxide (CO) and haemoglobin that forms in red blood cells when CO gas is inhaled or produced during haem catabolism. An elevated COHb content in blood is considered a biomarker of CO exposure.

Cellular bioenergetics

Biochemical processes, such as respiration and metabolism, involved in energy flow through all organisms. Fluctuations in cellular bioenergetics dictate growth and survival, and are dependent on appropriate transformation and utilization of energy such as ATP.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Motterlini, R., Otterbein, L. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov 9, 728–743 (2010). https://doi.org/10.1038/nrd3228

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3228

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research