A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning.
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ABSTRACT:
SUBMITTER: Rose JJ
PROVIDER: S-EPMC7212636 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Carbon monoxide (CO) is a leading cause of poisoning deaths worldwide, with no available antidotal therapy. We introduce a potential treatment paradigm for CO poisoning, based on near-irreversible binding of CO by an engineered human neuroglobin (Ngb). Ngb is a six-coordinate hemoprotein, with the heme iron coordinated by two histidine residues. We mutated the distal histidine to glutamine (H64Q) and substituted three surface cysteines with less reactive amino acids to form a five-coordinate heme protein (Ngb-H64Q-CCC). This molecule exhibited an unusually high affinity for gaseous ligands, with a P50 (partial pressure of O2 at which hemoglobin is half-saturated) value for oxygen of 0.015 mmHg. Ngb-H64Q-CCC bound CO about 500 times more strongly than did hemoglobin. Incubation of Ngb-H64Q-CCC with 100% CO-saturated hemoglobin, either cell-free or encapsulated in human red blood cells, reduced the half-life of carboxyhemoglobin to 0.11 and 0.41 min, respectively, from ?200 min when the hemoglobin or red blood cells were exposed only to air. Infusion of Ngb-H64Q-CCC to CO-poisoned mice enhanced CO removal from red blood cells, restored heart rate and blood pressure, increased survival, and was followed by rapid renal elimination of CO-bound Ngb-H64Q-CCC. Heme-based scavenger molecules with very high CO binding affinity, such as our mutant five-coordinate Ngb, are potential antidotes for CO poisoning by virtue of their ability to bind and eliminate CO.
| S-EPMC5206801 | biostudies-literature
Project description:Carbon monoxide (CO) is the leading cause of poisoning deaths in many countries, including Japan. Annually, CO poisoning claims about 2000-5000 lives in Japan, which is over half of the total number of poisoning deaths. This paper discusses the physicochemical properties of CO and the toxicological evaluation of CO poisoning.
| S-EPMC6992844 | biostudies-literature
Project description:The severity of acute carbon monoxide (CO) poisoning is often based on non-specific clinical criteria because there are no reliable laboratory markers. We hypothesized that a pattern of plasma protein values might objectively discern CO poisoning severity. This was a pilot study to evaluate protein profiles in plasma samples collected from patients at the time of initial hospital evaluation. The goal was to assess whether any values differed from age- and sex-matched controls using a commercially available plasma screening package.Frozen samples from 63 suspected CO poisoning patients categorized based on clinical signs, symptoms, and blood carboxyhemoglobin level were analyzed along with 42 age- and sex-matched controls using Luminex-based technology to determine the concentration of 180 proteins.Significant differences from control values were found for 99 proteins in at least one of five CO poisoning groups. A complex pattern of elevations in acute phase reactants and proteins associated with inflammatory responses including chemokines/cytokines and interleukins, growth factors, hormones, and an array of auto-antibodies was found. Fourteen protein values were significantly different from control in all CO groups, including patients with nominal carboxyhemoglobin elevations and relatively brief intervals of exposure.The data demonstrate the complexity of CO pathophysiology and support a view that exposure causes acute inflammatory events in humans. This pilot study has insufficient power to discern reliable differences among patients who develop neurological sequelae but future trials are warranted to determine whether plasma profiles predict mortality and morbidity risks of CO poisoning.
| S-EPMC3941305 | biostudies-literature
Project description:BACKGROUND:Poisoning with carbon monoxide (CO) remains an important cause of accidental and intentional injury worldwide. Several unblinded non-randomized trials have suggested that the use of hyperbaric oxygen (HBO) prevents the development of neurological sequelae. This has led to the widespread use of HBO in the management of patients with carbon monoxide poisoning. OBJECTIVES:To examine randomised trials of the efficacy of hyperbaric oxygen (HBO) compared to normobaric oxygen (NBO) for the prevention of neurologic sequelae in patients with acute carbon monoxide poisoning. SEARCH STRATEGY:We searched the following electronic databases; Cochrane Injuries Group Specialised Register (searched June 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE (Ovid SP) 1950 to June 2010, EMBASE (Ovid SP) 1980 to June 2010, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to June 2010, ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) 1990 to June 2010. SELECTION CRITERIA:All randomised controlled trials of HBO compared to NBO, involving non-pregnant adults who are acutely poisoned with carbon monoxide (regardless of severity). DATA COLLECTION AND ANALYSIS:Two authors independently extracted from each trial information on: the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurologic symptoms at follow-up. MAIN RESULTS:Seven randomised controlled trials of varying quality were identified; one was excluded because it did not evaluate clinical outcomes. Of the six remaining trials involving 1361 participants, two found a beneficial effect of HBO for the reduction of neurologic sequelae at one month, while four others did not. One of these is an incomplete publication (an abstract of an interim analysis). Although pooled random effects meta-analysis does not suggest a significant benefit from HBOT (OR for neurological deficits 0.78, 95%CI 0.54 to 1.12), significant methodologic and statistical heterogeneity was apparent among the trials, and this result should be interpreted cautiously. Moreover, design or analysis flaws were evident in all trials. Importantly, the conclusions of one positive trial may have been influenced by failure to adjust for multiple hypothesis testing, while interpretation of the other positive trial is hampered by a high risk of bias introduced during the analysis including an apparent change in the primary outcome. Both were also stopped early 'for benefit', which is likely to have inflated the observed effect. In contrast three negative trials had low power to detect a benefit of HBO due to exclusion of severely poisoned patients in two and very poor follow-up in the other. One trial that was said to be finished around eight years ago has not reported the final analysis in any forum. AUTHORS' CONCLUSIONS:Existing randomised trials do not establish whether the administration of HBO to patients with carbon monoxide poisoning reduces the incidence of adverse neurologic outcomes. Additional research is needed to better define the role, if any, of HBO in the treatment of patients with carbon monoxide poisoning. This research question is ideally suited to a multi-center randomised controlled trial.
| S-EPMC7066484 | biostudies-literature
Project description:Carbon monoxide (CO) is generated during incomplete combustion of carbon-containing compounds and leads to acute and chronic toxicity in animals and humans depending on the concentration and exposure time. In addition to exogenous sources, CO is also produced endogenously by the activity of heme oxygenases (HOs) and the physiological significance of HO-derived CO has only recently emerged. CO exerts vasoactive, anti-proliferative, anti-oxidant, anti-inflammatory and anti-apoptotic effects and contributes substantially to the important role of the inducible isoform HO-1 as a mediator of tissue protection and host defense. Exogenous application of low doses of gaseous CO might provide a powerful tool to protect organs and tissues under various stress conditions. Experimental evidence strongly suggests a beneficial effect under pathophysiological conditions such as organ transplantation, ischemia/reperfusion, inflammation, sepsis, or shock states. The cellular and molecular mechanisms mediating CO effects are only partially characterized. So far, only a few studies in humans are available, which, however, do not support the promising results observed in experimental studies. The protective effects of exogenous CO may strongly depend on the pathological condition, the mode, time point and duration of application, the administered concentration, and on the target tissue and cell. Differences in bioavailability of endogenous CO production and exogenous CO supplementation might also provide an explanation for the lack of protective effects observed in some experimental and clinical studies. Further randomized, controlled clinical studies are needed to clarify whether exogenous application of CO may turn into a safe and effective preventive and therapeutic strategy to treat pathophysiological conditions associated with inflammatory or oxidative stress.
| S-EPMC2750131 | biostudies-other
Project description:BACKGROUND:The symptoms of carbon monoxide (CO) poisoning are nonspecific, ranging from dizziness and headache to unconsciousness and death. A German national guideline on the diagnosis and treatment of this condition is lacking at present. METHODS:This review is based on a selective literature search in the PubMed and Cochrane databases, as well as on existing guidelines from abroad and expert recommendations on diagnosis and treatment. RESULTS:The initiation of 100% oxygen breathing as early as possible is the most important treatment for carbon monoxide poisoning. In case of CO poisoning, the reduced oxygen-carrying capacity of the blood, impairment of the cellular respiratory chain, and immune-modulating processes can lead to tissue injury in the myocardium and brain even after lowering of the carboxyhemoglobin (COHb) concentration. In patients with severe carbon monoxide poisoning, an ECG should be obtained and biomarkers for cardiac ischemia should be measured. Hyperbaric oxygen therapy (HBOT) should be critically considered and initiated within six hours in patients with neurologic deficits, unconsciousness, cardiac ischemia, pregnancy, and/or a very high COHb concentration. At present, there is no general recommendation for HBOT, in view of the heterogeneous state of the evidence from multiple trials. Therapeutic decision-making is directed toward the avoidance of sequelae such as cognitive dysfunction and cardiac complications, and the reduction of mortality. Smoke intoxication must be considered in the differential diagnosis. The state of the evidence on the diagnosis and treatment of this condition is not entirely clear. Alternative or supplementary pharmacological treatments now exist only on an experimental basis. CONCLUSION:High-quality, prospective, randomized trials that would enable a definitive judgment of the efficacy of HBOT are currently lacking.
| S-EPMC6381775 | biostudies-literature
Project description:RationaleWe hypothesized that platelet-neutrophil interactions occur as a result of acute carbon monoxide (CO) poisoning, and subsequent neutrophil activation triggers events that cause neurologic sequelae.ObjectivesTo identify platelet-neutrophil interactions and neutrophil activation in patients and in animal models, and to establish the association between these intravascular events and changes linked to CO-mediated neurologic sequelae in an animal model.Measurements and main resultsBlood was obtained from 50 consecutive patients. Abnormalities were variable depending on the carboxyhemoglobin level at study admission and duration of CO exposure. Platelet-neutrophil aggregates were detected and plasma myeloperoxidase (MPO) concentration was significantly elevated in those with confirmed CO poisoning. Among patients exposed to CO for over 3 h, flow cytometry scans of neutrophils revealed increased surface expression of CD18 and, in some groups, MPO on the cell surface. Animal models revealed consistent evidence of platelet-neutrophil aggregates, neutrophil activation and surface MPO, and plasma MPO elevation. MPO was deposited along the brain vascular lining and colocalized with nitrotyrosine. CO poisoning caused abnormalities in the charge pattern of myelin basic protein (MBP), changes linked to adaptive immunologic responses responsible for neurologic sequelae in this model. Changes did not occur in thrombocytopenic rats, those receiving tirofiban to inhibit platelet-neutrophil interactions, or those receiving L-nitroarginine methyl ester to inhibit nitric oxide synthesis. Alterations in MBP did not occur in CO-poisoned knockout mice lacking MPO.ConclusionsAcute CO poisoning causes intravascular neutrophil activation due to interactions with platelets. MPO liberated by neutrophils mediates perivascular oxidative stress, which is linked to immune-mediated neurologic sequelae.
| S-EPMC2648106 | biostudies-literature
Project description:We have proposed the existence of a threshold for brain damage, in terms of hydroxyl radical production in rat striatum, between poisoning of carbon monoxide (CO) at 1000 ppm and 3000 ppm, where blood CO-hemoglobin levels reach approximately 50% and over 70%, respectively. To search for factors involved in brain damage, we examined the effects of air, 1000 ppm CO, 3000 ppm CO and 5% O2 (hypoxic conditions comparable with those by 3000 ppm CO) on gene expression in rat striatum, using microarray analysis.
2017-04-03 | GSE94780 | GEO
Project description:Carbon monoxide (CO) can occur in numerous situations and ambient conditions, such as fire smoke, indoor fireplaces, silos containing large quantities of wood pellets, engine exhaust fumes, and when using hookahs. Symptoms of CO poisoning are nonspecific and can range from dizziness, headache, and angina pectoris to unconsciousness and death. This guideline presents the current state of knowledge and national recommendations on the diagnosis and treatment of patients with CO poisoning. The diagnosis of CO poisoning is based on clinical symptoms and proven or probable exposure to CO. Negative carboxyhemoglobin (COHb) levels should not rule out CO poisoning if the history and symptoms are consistent with this phenomenon. Reduced oxygen-carrying capacity, impairment of the cellular respiratory chain, and immunomodulatory processes may result in myocardial and central nervous tissue damage even after a reduction in COHb. If CO poisoning is suspected, 100% oxygen breathing should be immediately initiated in the prehospital setting. Clinical symptoms do not correlate with COHb elimination from the blood; therefore, COHb monitoring alone is unsuitable for treatment management. Especially in the absence of improvement despite treatment, a reevaluation for other possible differential diagnoses ought to be performed. Evidence regarding the benefit of hyperbaric oxygen therapy (HBOT) is scant and the subject of controversy due to the heterogeneity of studies. If required, HBOT should be initiated within 6 h. All patients with CO poisoning should be informed about the risk of delayed neurological sequelae (DNS).
| S-EPMC8607608 | biostudies-literature
Project description:Carbon monoxide (CO) poisoning causes brain damage, which is attenuated by treatment with hydrogen [1], [2], a scavenger selective to hydroxyl radical (•OH) [3]. This suggests a role of •OH in brain damage due to CO poisoning. Studies have shown strong enhancement of •OH production in rat striatum by severe CO poisoning with a blood carboxyhemoglobin (COHb) level > 70% due to 3000 ppm CO, but not less severe CO poisoning with a blood COHb level at approximately 50% due to 1000 ppm CO [4]. Interestingly, 5% O2 causes hypoxia comparable with that by 3000 ppm CO and produces much less •OH than 3000 ppm CO does [4]. In addition, cAMP production in parallel with •OH production [5] might contribute to •OH production [6]. It is likely that mechanisms other than hypoxia contribute to brain damage due to CO poisoning [7]. To search for the mechanisms, we examined the effects of 1000 ppm CO, 3000 ppm CO and 5% O2 on gene expression in rat striatum. All array data have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE94780.
| S-EPMC5374847 | biostudies-literature