Abstract
Small amounts of carbon monoxide (CO) are continuously produced in mammals. The intracellular levels of this gaseous molecule can markedly increase under stressful conditions following the induction of heme oxygenases (HO), ubiquitous enzymes responsible for the catabolism of heme. The development of a technology concerning the CO-releasing molecules (CO-RMs) that control the delivery and action of CO under different pathological conditions represents a major step forward in the development of CO-based pharmaceuticals with therapeutic applications. CO is important for the homeostatic control of cardiovascular functions. Abnormal metabolism and function of CO contribute to the pathogenesis and development of hypertension. Another vascular disease in which the role of CO has been evaluated is pulmonary arterial hypertension. Important results have been reported in which CO prevents intimal hyperplasia by arresting hyperproliferative vascular smooth muscle cells as well as increased mobilization and recruitment of bone-marrow-derived progenitor cells. Transplantation has been a field of research, in which most studies have investigated the beneficial properties of CO-RMs. CO gas and CO-RMs have produced promising results in the preservation of organs for transplantation. The anti-inflammatory properties of CO and CO-RMs have been demonstrated in a multitude of animal models of inflammation, suggesting a possible therapeutic application for inflammatory diseases. Despite therapeutic benefit in animal model studies, the efficacy of CO in humans remains unclear. Further studies are expected to better understand the pharmacokinetics as well as long- and short-term effects of CO-RMs.
Résumé
Du monoxyde de carbone (CO) est continuellement produit en petites quantités chez les mammifères. Le niveau intracellulaire de cette molécule gazeuse augmente de façon significative en conditions de stress, après induction des hèmes oxygénases (HO), enzymes ubiquitaires responsables du catabolisme de l’hème. Pouvoir disposer de molécules libérant du CO (MLCO), avec la possibilité de maîtrise de ses conditions de production et d’action, représente une étape essentielle pour le développement de médicaments à base de CO pouvant déboucher sur des applications thérapeutiques. Le CO joue un rôle important dans le contrôle homéostatique des fonctions cardiovasculaires. Toute altération du métabolisme ou de l’utilisation du CO peut contribuer au développement d’une hypertension. L’hypertension artérielle pulmonaire est l’une de ces conditions pathologiques où le CO joue un rôle mécanistique significatif. Des données importantes ont été publiées, démontrant que le CO prévient l’hyperplasie intimale en stoppant la prolifération des cellules musculaires lisses et en inhibant l’augmentation de mobilisation et de recrutement de cellules souches progénitrices dérivant de la moelle osseuse. La transplantation est un domaine de recherche où plusieurs études ont montré le bénéfice de ces MLCO. Le CO et les MLCO sont à l’origine de résultats prometteurs dans le champ de la préservation des organes pour la greffe. Les propriétés anti-inflammatoires du CO et des MLCO ont été retrouvées dans de nombreuses études, au travers de modèles animaux d’inflammation, suggérant ainsi de possibles applications dans le traitement des pathologies inflammatoires. Néanmoins et malgré un bénéfice thérapeutique établi expérimentalement, l’intérêt du CO chez l’homme reste incertain. Des études à venir sont encore attendues pour permettre un progrès des connaissances tant pour la pharmacocinétique que pour les effets à court et à long terme des MLCO.
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Cet article correspond à la conférence faite par l’auteur au congrès de la SRLF 2012 dans la session: Plein gaz.
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Rochette, L., Vergely, C., Rochette, F. et al. Carbon monoxide: a new pharmaceutical agent?. Réanimation 21 (Suppl 2), 460–466 (2012). https://doi.org/10.1007/s13546-011-0430-4
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DOI: https://doi.org/10.1007/s13546-011-0430-4