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• W2011043948 abstract "The paper by Andersson et al. published in this issue provides further evidence of the importance of carbon monoxide (CO) as an endogenously produced molecule [1]. A decade ago, carbon monoxide was known only as a lethal gas. However, since then it has been established as an important signalling molecule, produced in various cell types throughout the body. A better understanding of the role of CO as a signalling molecule could provide insight into the toxic mechanisms involved in CO poisoning. While hypoxia is generally held accountable for most of the effects experienced by victims of CO poisoning, some remain to be explained [2-4]. It has been suggested that CO functions as a neural messenger in the brain, and thus exposure to an external source of CO might interfere with signalling and cause neurological disturbance [5]. Carbon monoxide is produced in vivo by the catabolism of heme to yield CO and biliverdin, two molecules previously thought to be byproducts [6, 7]. This process is activated by the enzyme heme oxygenase (HO), of which there are two isoforms: HO1 and HO2. HO1 is found mainly in the spleen, where it degrades heme from senescent red blood cells. It can be induced by many agents, such as heme, inflammatory cytokines, prostaglandins, hormones and by oxidative stress and hypoxia [7, 8]. HO2 is the constitutive form of the enzyme and is present in neurones [7, 8], endothelium and gastrointestinal tract [9] and testes [6]. Protein Kinase C, which is activated by neuronal depolarization, phosphorylates and activates HO2[6], thus providing a mechanism for the rapid formation of CO. CO is known, for example in olfactory cells, to activate cytoplasmic guanylyl cyclase (cGC), leading to an increase in cyclic guanosine monophosphate (cGMP) [10]. However, there is also evidence indicating that CO plays a role in at least one cGMP-independent pathway, involving mitogen-activated protein kinases [11]. There is also controversy over the role of CO in cells in which nitric oxide (NO) concentrations regulate cGC activity. Despite the fact that CO per se activates cGC, inhibition of CO production did not lead to a fall in cGMP levels. Ingi et al. [12] argued that in such cells, CO inhibited the effect of NO on cGMP production. The mechanism for this is unclear and might include the inhibition of NO synthase by CO, thus reducing the production of NO, or interference with the interaction between NO and cGC. Endogenously produced CO is thought to be involved in many processes, including smooth muscle relaxation mediated by the enteric nervous system. For example, this effect was observed in guinea-pigs in vitro[13]. Since heme oxygenase was found in the interstitial cells of Cajal, CO is thought to act as a messenger between these cells and gastrointestinal smooth muscle cells [9]. Further evidence stems from a study by the same group, who found that knockout mice lacking the biosynthetic enzymes necessary to produce CO had depolarized neurons and decreased muscle relaxation due to reduced inhibitory junctional potentials [14]. Thus one function of CO is thought to be the inhibition of muscle contraction in the gut, where it acts as a signalling molecule at the neuromuscular junction. CO is also known to be involved in vasodilation [15, 16] and studies have shown that CO causes bronchodilation in guinea-pigs [17, 18] and has a role in modulating blood pressure under stress conditions in vivo[19]. There is recent evidence that CO is involved in signalling in the carotid body. Prabhakar et al. [20] found that HO2 was localized to glomus cells of rat and cat carotid bodies. HO2 inhibition caused an increase in carotid body activity, a response which was attenuated by the addition of exogenous CO. This study suggests that CO functions as an inhibitor of carotid body activity. However, the mechanism by which this occurs is still unclear. One possible explanation is that CO regulates the release of an excitatory neurotransmitter. CO could also affect vasodilation, which would lead to increased local oxygenation. Besides its role as a signalling molecule in the peripheral nervous system, CO has more recently been implicated as a neurotransmitter in the brain. CO is found in large amounts in the brain, particularly in the hippocampus, cerebellum and olfactory cells [8]. Of the neuroendocrine tissues, the hypothalamus has the highest CO production rate in the brain [21]. These observations have prompted investigation into the possible role of CO as a mediator of long-term potentiation (LTP) and as a neuroendocrine modulator. There is evidence, though controversial, that CO is involved in the induction of LTP, a process that leads to an increase in synaptic efficiency in the hippocampus, believed to be important for learning and memory. It is thought that CO might act as a retrograde messenger, by delivering information from the post-synaptic to the pre-synaptic neuron, leading to an increase in transmitter release. HO2 inhibitors blocked the induction of LTP in the CA1 region of the hippocampal slices [22-24], and attenuated LTP in the dentate gyrus [25]. However, a study by Poss et al. [26] showed that LTP was not affected in knockout mice lacking the gene for HO2. As the results are inconsistent and the mechanism by which CO is involved in LTP is still unknown, it is unclear whether CO has a role in LTP. CO also appears to have a neuromodulatory effect in the hypothalamus. A study in female rats has shown that CO plays a role in the release of gonadotropin-releasing hormone (GnRH) [27]. GnRH release was stimulated in hypothalamus preparations incubated with HO and haematin, a heme molecule cleaved by HO to yield CO. As both a heme oxygenase inhibitor and a CO-scavenger molecule blocked this effect, GnRH release was thought to be mediated by CO. CO is also thought to act as an inhibitory neurotransmitter involved in oxytocin release from rat hypothalamus [28]. The study showed that when rat hypothalamus was incubated with hemin, a substrate of heme oxygenase, KCl- or serotonin-stimulated oxytocin release was inhibited. The evidence suggested that CO was responsible for the modulating action. Another role for CO in the hypothalamus is in mediating the release of corticotropin-releasing hormone (CRH) [29, 30], however, there is controversy over what the effect might be [28]. In support of other studies showing an inhibitory role for CO in the neuroendocrine axis, hemin dose-dependantly inhibited KCl- and IL-1β-stimulated CRH release in vitro[29]. While more studies are needed to clarify the role of CO, it seems possible that CO regulates the release of hormones from the hypothalamus. CO might also be involved in inflammatory processes. A study by Otterbein et al. [11] reported that CO could be responsible for anti-inflammatory effects associated with HO1. CO inhibited the expression of pro-inflammatory cytokines (TNF-α, IL-1β, MIP-1β), while increasing the expression of the anti-inflammatory cytokine IL-10, both in vivo and in vitro. CO mediated these effects not through cGMP but through mitogen-activated protein kinases. A study by Andersson et al. [31] demonstrated that CO was produced endogenously in the nose and paranasal sinuses in humans, and is probably involved in upper and lower airway regulation and inflammation. HO1 and high levels of HO2 were measured in the respiratory epithelium and in connection with smooth muscle of arteries and veins in the submucosa. In their most recent paper (published in this issue) [1], they report increased levels of exhaled CO in patients with upper respiratory tract infection or allergic rhinitis. This further supports the idea that CO is involved in upper airway inflammation, and might function as a mediator. Their results agree with the findings of Otterbein et al. [11], who reported anti-inflammatory effects of CO. CO has also been found in macrophages. Arias-D'iaz et al. [32] investigated the capacity of human pulmonary macrophages to produce CO. In the presence of LPS (lipopolysaccharide), TNF-α production was accompanied by an increase in CO concentration and cell cGMP content. CO is thought to be involved in the production of cGMP in pulmonary macrophages, and could be involved in lung defence against endotoxic shock [15]. An interesting and somewhat ironic point about carbon monoxide is that it seems to be associated both with causing oxidative stress and with producing protective effects during stress conditions. Many studies have shown that hypoxia caused by accidental inhalation of CO is associated with increased oxidative stress compared with that caused by lack of oxygen alone [5, 33]. Under hypoxic conditions, xanthine dehydrogenase is converted to xanthine oxidase, which produces superoxide radicals and hydrogen peroxide, followed by lipid peroxidation [34]. Another pathway thought to cause oxidative stress involves the binding of CO to reduced cytochrome c oxidase in the mitochondria. This binding interferes with the electron transport chain and leads to the production of partially reduced oxidative species [35]. On the other hand, it has been shown that the expression of HO1 is increased under stress conditions, including oxidative stress and inflammation [15]. During hypoxic stress, CO is increased sevenfold in vascular smooth muscle cells, and is thought to produce vasodilation in response to hypoxia. It is surprising that CO is thought to have a protective effect during hypoxia, when it is often CO itself that is responsible for hypoxia. Much of the role of CO in the body remains a mystery. This single molecule is thought to be involved in smooth muscle relaxation, memory formation, hormone release in the hypothalamus and inflammation. It is clear that it often functions as a signalling molecule, and sometimes has an inhibitory role. But the full picture is far from clear. Studies providing new information about CO are appearing frequently, and it is becoming increasingly apparent that CO is a very versatile molecule. As many of the pathways remain unclear, it is difficult to understand how CO can be involved in so many different processes." @default.
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• W2011043948 title "Changing views on carbon monoxide*" @default.
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