![]() The pure substance of carbon monoxide itself may alter various diseases in all kinds of experimental physiological systems, settings, and target-organs (i.e., anti-inflammatory, anti-apoptotic, anti-oxidative, anti-proliferative, and vasodilative etc.) see Fig. Among various agents in question, anesthetics (e.g., isoflurane and sevoflurane) were found to be capable of a significant HO-1 induction providing not only an upregulation of HO-1, but also organ protection, while being clinically safe. Since CO is thought to be the crucial product of the HO breakdown, a generation of scientist was in search for non-toxic but yet potent HO-1 inducible drugs. While the knowledge of significance only emerged slowly over the years, it was in 1999 that the case of a child with proven HO-1 deficiency was reported, suffering from a variety of organ dysfunction. Haem-oxygenase-1 and -2 (HO-1 and -2) have been demonstrated to be the (stress-) inducible and constitutive isoforms of the rate-limiting enzyme, responsible to produce CO. Tenhunen and Schmidt first identified the enzyme responsible to produce CO endogenously: hemoxygenase (HO). The finding, that the catalytic degradation and conversion of hemoglobin into its parts (i.e., biliverdin, iron and carbon monoxide) is an enzyme-triggered process directed research into a new direction. Since its discovery as an endogenously generated product in the degradation process of haem, a multitude of in-vitro and in-vivo experiments have been performed to analyse its effects in a variety of systems and diseases and shed light on the impact as well as the molecular mechanism of this interesting gas. Although different symptoms of CO intoxications were seen (ranging from headache and fatigue to nausea and vomiting, confusion, and convulsion and finally death), it took more than 50 years to prove Paracelsus’ maxim to be true: “only the dose makes the poison.”Ĭarbon monoxide was recognized and first described in 1925 to be more than just a toxic, odorless and thus very dangerous gaseous molecule. The high affinity of CO to hemoglobin was used as one possible explanation for the toxic effects. In this paper, we summarized the current understanding of carbon monoxide’s biology and its possible organ targets to treating the critically ill patients in tomorrow’s ICU.īeing an odorless and difficult to sense gas, carbon monoxide (CO) was usually referred to as the “silent killer” with a myriad of published and unpublished fatal accidents, mostly due to incomplete combustion of organic material or explosions. Carbon monoxide is a most promising candidate in terms of a therapeutic agent to improve outbalanced organ conditions. Current models of human research include sepsis, acute lung injury, and acute respiratory distress syndrome as well as acute kidney injury. Up-to-date, safety issues have been cleared for low-dose carbon monoxide inhalation (up to 500 ppm), while there is no clinical data regarding the injection or intake of any kind of CO-RM so far. After years of research in cellular systems and animal models, summing up data about safety issues as well as possible target to treat in various diseases, the first feasibility trials in humans were established. Since HO-1 is not easy to induce, research focused on the application of the gaseous molecule CO by itself or the implementation of carbon monoxide releasing molecules (CO-RM) to deliver the molecule at a time- and dose dependently safe way to any target organ. With our growing understanding in the way CO exerts its effects, especially in the mitochondria and its intracellular pathways, it is tempting to speculate about a clinical application of this substance. Carbon monoxide is able to modulate several extra- and intra-cellular signaling molecules leading to differentiated response according to the specific stimulus. Among these, the modulation of various systems inside the body are well described (e.g., anti-inflammatory, anti-oxidative, anti-apoptotic, and anti-proliferative). ![]() For decades, scientists established evidence about its endogenously production in the breakdown of haem via haem-oxygenase (HO-1) and its physiological effects. Carbon monoxide (CO) is not only known as a toxic gas due to its characteristics as an odorless molecule and its rapid binding to haem-containing molecules, thus inhibiting the respiratory chain in cells resulting in hypoxia. ![]()
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