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The therapeutic potential of carbon monoxide

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.

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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.

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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.

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

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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.

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

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