Recent progress on anti-nociceptive effects of carbon monoxide releasing molecule-2 (CORM-2).

The role of carbon monoxide (CO) has evolved albeit controversial disputes on its toxicity. This biological gasotransmitter participates in the endogenous regulation of neurotransmitters and neuropeptides released in the nervous system. Exogenous CO gas inhalation at a lower concentration has been the subject of investigations, which have revealed its biological homeostatic mechanisms and protective effects against many pathological conditions. This therapeutic procedure of CO is, however, limited due to its immediate release, which favours haemoglobin at a high affinity with the subsequent generation of toxic carboxyhaemoglobin in tissues. In order to address this problem, carbon monoxide releasing molecule-2 (CORM-2) or also known as tricarbonyldichlororuthenium II dimer is developed to liberate a controlled amount of CO in the biological systems. In this review, we examine several potential mechanisms exerted by this therapeutic compound to produce the anti-nociceptive effect that has been demonstrated in previous studies. This review could shed light on the role of CORM-2 to reduce pain, especially in cases of chronic and neuropathic pain.

The association between transfer coefficient of the lung and the risk of exacerbation in asthma-COPD overlap: an observational cohort study.

BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) patients experience exacerbations more frequently than those with asthma or COPD alone. Since low diffusing capacity of the lung for carbon monoxide (DLCO) is known as a strong risk factor for severe exacerbation in COPD, DLCO or a transfer coefficient of the lung for carbon monoxide (KCO) is speculated to also be associated with the risk of exacerbations in ACO. METHODS: This study was conducted as an observational cohort survey at the National Hospital Organization Fukuoka National Hospital. DLCO and KCO were measured in 94 patients aged ≥ 40 years with a confirmed diagnosis of ACO. Multivariable-adjusted hazard ratios (HRs) for the exacerbation-free rate over one year were estimated and compared across the levels of DLCO and KCO. RESULTS: Within one year, 33.3% of the cohort experienced exacerbations. After adjustment for potential confounders, low KCO (< 80% per predicted) was positively associated with the incidence of exacerbation (multivariable-adjusted HR = 3.71 (95% confidence interval 1.32-10.4)). The association between low DLCO (< 80% per predicted) and exacerbations showed similar trends, although it failed to reach statistical significance (multivariable-adjusted HR = 1.31 (95% confidence interval 0.55-3.11)). CONCLUSIONS: Low KCO was a significant risk factor for exacerbations among patients with ACO. Clinicians should be aware that ACO patients with impaired KCO are at increased risk of exacerbations and that careful management in such a population is mandatory.

A brief history of carbon monoxide and its therapeutic origins.

It is estimated that 10% of carbon throughout the cosmos is in the form of carbon monoxide (CO). Earth's earliest prebiotic atmosphere included the trinity of gasotransmitters CO, nitric oxide (NO), and hydrogen sulfide (H2S), for which all of life has co-evolved with. The history of CO can be loosely traced to mythological and prehistoric origins with rudimentary understanding emerging in the middle ages. Ancient literature is focused on CO's deadly toxicity which is understandable in the context of our primitive relationship with coal and fire. Scientific inquiry into CO appears to have emerged throughout the 1700s followed by chemical and toxicological profiling throughout the 1800s. Despite CO's ghastly reputation, several of the 18th and 19th century scientists suggested a therapeutic application of CO. Since 2000, the fundamental understanding of CO as a deadly nuisance has undergone a paradigm shift such that CO is now recognized as a neurotransmitter and viable pharmaceutical candidate. This review is intended to provide a brief history on the trace origins pertaining to endogenous formation and therapeutic application of CO.

Prognostic marker for severe acute exacerbation of chronic obstructive pulmonary disease: analysis of diffusing capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in one second (FEV1).

BACKGROUND: It is important to assess the prognosis of patients with chronic obstructive pulmonary disease (COPD) and acute exacerbation of COPD (AECOPD). Recently, it was suggested that diffusing capacity of the lung for carbon monoxide (DLCO) should be added to multidimensional tools for assessing COPD. This study aimed to compare the DLCO and forced expiratory volume in one second (FEV1) to identify better prognostic factors for admitted patients with AECOPD. METHODS: We retrospectively analyzed 342 patients with AECOPD receiving inpatient treatment. We classified 342 severe AECOPD patients by severity of DLCO and FEV1 (≤ vs. > 50% predicted). We tested the association of FEV1 and DLCO with the following outcomes: in-hospital mortality, need for mechanical ventilation, need for intensive care unit (ICU) care. We analyzed the prognostic factors by multivariate analysis using logistic regression. In addition, we conducted a correlation analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: In multivariate analyses, DLCO was associated with mortality (odds ratio = 4.408; 95% CI 1.070-18.167; P = 0.040) and need for mechanical ventilation (odds ratio = 2.855; 95% CI 1.216-6.704; P = 0.016) and ICU care (odds ratios = 2.685; 95% CI 1.290-5.590; P = 0.008). However, there was no statistically significant difference in mortality rate when using FEV1 classification (P = 0.075). In multivariate linear regression analyses, DLCO (B = - 0.542 ± 0.121, P < 0.001) and FEV1 (B = - 0.106 ± 0.106, P = 0.006) were negatively associated with length of hospital stay. In addition, DLCO showed better predictive ability than FEV1 in ROC curve analysis. The area under the curve (AUC) of DLCO was greater than 0.68 for all prognostic factors, and in contrast, the AUC of FEV1 was less than 0.68. CONCLUSION: DLCO was likely to be as good as or better prognostic marker than FEV1 in severe AECOPD.

Gaseous Signaling Molecules in Cardiovascular Function: From Mechanisms to Clinical Translation.

Carbon monoxide (CO), hydrogen sulfide (H2S), and nitric oxide (NO) constitute endogenous gaseous molecules produced by specific enzymes. These gases are chemically simple, but exert multiple effects and act through shared molecular targets to control both physiology and pathophysiology in the cardiovascular system (CVS). The gases act via direct and/or indirect interactions with each other in proteins such as heme-containing enzymes, the mitochondrial respiratory complex, and ion channels, among others. Studies of the major impacts of CO, H2S, and NO on the CVS have revealed their involvement in controlling blood pressure and in reducing cardiac reperfusion injuries, although their functional roles are not limited to these conditions. In this review, the basic aspects of CO, H2S, and NO, including their production and effects on enzymes, mitochondrial respiration and biogenesis, and ion channels are briefly addressed to provide insight into their biology with respect to the CVS. Finally, potential therapeutic applications of CO, H2S, and NO with the CVS are addressed, based on the use of exogenous donors and different types of delivery systems.

Maternal disease and gasotransmitters.

The three known gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide are involved in key processes throughout pregnancy. Gasotransmitters are known to impact on smooth muscle tone, regulation of immune responses, and oxidative state of cells and their component molecules. Failure of the systems that tightly regulate gasotransmitter production and downstream effects are thought to contribute to common maternal diseases such as preeclampsia and preterm birth. Normal pregnancy-related changes in uterine blood flow depend heavily on gasotransmitter signaling. In preeclampsia, endothelial dysfunction is a major contributor to aberrant gasotransmitter signaling, resulting in hypertension after 20 weeks gestation. Maintenance of pregnancy to term also requires gasotransmitter-mediated uterine quiescence. As the appropriate signals for parturition occur, regulation of gasotransmitter signaling must work in concert with those endocrine signals in order for appropriate labor and delivery timing. Like preeclampsia, preterm birth may have origins in abnormal gasotransmitter signaling. We review the evidence for the involvement of gasotransmitters in preeclampsia and preterm birth, as well as mechanistic and molecular signaling targets.

Combined diffusing capacity for nitric oxide and carbon monoxide as predictor of bronchiolitis obliterans syndrome following lung transplantation.

BACKGROUND: There is a need for non-invasive parameters that are sensitive to the development of the bronchiolitis obliterans syndrome (BOS) in lung transplantation (LTx) patients. We studied whether the pulmonary diffusing capacity for inhaled nitric oxide is capable of detecting BOS stages. METHODS: Sixty-one LTx patients were included into this cross-sectional study (19/29/7/3/3 in BOS stages 0/0-p/1/2/3). For analysis stages 0/0-p versus 1/2/3 ("BOS binary-early"), and stages 0/0-p/1 versus 2/3 ("BOS binary-late") were summarized. Measurements of the combined diffusing capacity for nitric oxide (DLNO) and carbon monoxide (DLCO) were compared with spirometry and bodyplethysmography, and their relative importance was evaluated by discriminant analysis. RESULTS: Regarding the recognition of "BOS binary-early", among spirometric parameters forced expiratory volume in 1 s (FEV1) was best, among bodyplethysmographic parameters airway resistance, and among diffusing parameters DLNO. Regarding "BOS binary-late", DLNO was inferior to bodyplethysmographic parameters. CONCLUSION: Although the study comprised only measurements at a single time point and no follow-up, DLNO outperformed FEV1, the time course of which is used in detecting BOS. Together with its pathophysiological plausibility, this result suggests that the measurement of DLNO, possibly over time, could be an easily applicable tool for the monitoring of LTx patients and should be evaluated in larger studies.

Heme oxygenase-1/biliverdin/carbon monoxide pathway downregulates hypernociception in rats by a mechanism dependent on cGMP/ATP-sensitive K+ channels.

OBJECTIVE AND DESIGN: To investigate the role of heme oxygenase-1 (HO-1), carbon monoxide (CO), and biliverdin (BVD) in the zymosan-induced TMJ arthritis in rats. MATERIALS AND METHODS: Mechanical threshold was assessed before and 4 h after TMJ arthritis induction in rats. Cell influx, myeloperoxidase activity, and histological changes were measured in the TMJ lavages and tissues. Trigeminal ganglion and periarticular tissues were used for HO-1, TNF-α, and IL-1ß mRNA time course expression and immunohistochemical analyses. Hemin (0.1, 0.3, or 1 mg kg-1), DMDC (0.025, 0.25, or 2.5 µmol kg-1), biliverdin (1, 3, or 10 mg kg-1), or ZnPP-IX (1, 3 or 9 mg kg-1) were injected (s.c.) 60 min before zymosan. ODQ (12.5 µmol kg-1; s.c.) or glibenclamide (10 mg kg-1; i.p.) was administered 1 h and 30 min prior to DMDC (2.5 µmol kg-1; s.c), respectively. RESULTS: Hemin (1 mg kg-1), DMDC (2.5 µmol kg-1), and BVD (10 mg kg-1) reduced hypernociception and leukocyte migration, which ZnPP (3 mg kg-1) enhanced. The effects of DMDC were counteracted by ODQ and glibenclamide. The HO-1, TNF-α, and IL-1ß mRNA expression and immunolabelling increased. CONCLUSIONS: HO-1/BVD/CO pathway activation provides anti-nociceptive and anti-inflammatory effects on the zymosan-induced TMJ hypernociception in rats.

2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung.

This document provides an update to the European Respiratory Society (ERS)/American Thoracic Society (ATS) technical standards for single-breath carbon monoxide uptake in the lung that was last updated in 2005. Although both DLCO (diffusing capacity) and TLCO (transfer factor) are valid terms to describe the uptake of carbon monoxide in the lung, the term DLCO is used in this document. A joint taskforce appointed by the ERS and ATS reviewed the recent literature on the measurement of DLCO and surveyed the current technical capabilities of instrumentation being manufactured around the world. The recommendations in this document represent the consensus of the taskforce members in regard to the evidence available for various aspects of DLCO measurement. Furthermore, it reflects the expert opinion of the taskforce members on areas in which peer-reviewed evidence was either not available or was incomplete. The major changes in these technical standards relate to DLCO measurement with systems using rapidly responding gas analysers for carbon monoxide and the tracer gas, which are now the most common type of DLCO instrumentation being manufactured. Technical improvements and the increased capability afforded by these new systems permit enhanced measurement of DLCO and the opportunity to include other optional measures of lung function.

Potential role of heme metabolism in the inducible expression of heme oxygenase-1.

BACKGROUND: The degradation of heme significantly contributes to cytoprotective effects against oxidative stress and inflammation. The enzyme heme oxygenase-1 (HO-1), involved in the degradation of heme, forms carbon monoxide (CO), ferrous iron, and bilirubin in conjunction with biliverdin reductase, and is induced by various stimuli including oxidative stress and heavy metals. We examined the involvement of heme metabolism in the induction of HO-1 by the inducers sulforaphane and sodium arsenite. METHODS: We examined the expression of HO-1 in sulforaphane-, sodium arsenite- and CORM3-treated HEK293T cells, by measuring the transcriptional activity and levels of mRNA and protein. RESULTS: The blockade of heme biosynthesis by succinylacetone and N-methyl protoporphyrin, which are inhibitors of heme biosynthesis, markedly decreased the induction of HO-1. The knockdown of the first enzyme in the biosynthesis of heme, 5-aminolevulinic acid synthase, also decreased the induction of HO-1. The cessation of HO-1 induction occurred at the transcriptional and translational levels, and was mediated by the activation of the heme-binding transcriptional repressor Bach1 and translational factor HRI. CO appeared to improve the expression of HO-1 at the transcriptional and translational levels. CONCLUSIONS: We demonstrated the importance of heme metabolism in the stress-inducible expression of HO-1, and also that heme and its degradation products are protective factors for self-defense responses. GENERAL SIGNIFICANCE: The key role of heme metabolism in the stress-inducible expression of HO-1 may promote further studies on heme and its degradation products as protective factors of cellular stresses and iron homeostasis in specialized cells, organs, and whole animal systems.

Reference values for pulmonary diffusing capacity for adult native Finns.

Measurement standards for pulmonary diffusing capacity were updated in 2005 by the ATS/ERS Task Force. However, in Finland reference values published in 1982 by Viljanen et al. have been used to date. The main aim of this study was to produce updated reference models for single-breath diffusing capacity for carbon monoxide for Finnish adults. Single-breath diffusing capacity for carbon monoxide was measured in 631 healthy non-smoking volunteers (41.5% male). Reference values for diffusing capacity (DLCO), alveolar volume (VA), diffusing capacity per unit of lung volume (DLCO/VA), and lung volumes were calculated using a linear regression model. Previously used Finnish reference values were found to produce too low predicted values, with mean predicted DLCO 111.0 and 104.4%, and DLCO/VA of 103.5 and 102.7% in males and females, respectively. With the European Coalition for Steel and Coal (ECSC) reference values there was a significant sex difference in DLCO/VA with mean predicted 105.4% in males and 92.8% in females (p < .001). New reference values for DLCO, DLCO/VA, VA, vital capacity (VC), inspiratory vital capacity (IVC), and inspiratory capacity (IC) are suggested for clinical use to replace technically outdated reference values for clinical applications.

Age-Specific Characteristics of CO-Mediated Reaction of the Pial Arteries of Various Diameters in Rats.

First-fourth order pial branches of the median cerebral artery were studied by biomicroscopy in male Wistar rats aged 1 and 12 months. Irrespective of age, CO-mediated mechanisms are involved in the regulation of the basal tone of pial vessels of various diameters (more so of arteries with well-developed muscular tunic). Injection of hemin confirmed that endogenous production of CO maintained vasodilatation and this effect was most pronounced in large pial branches of young animals, while zinc protoporphyrin IX blocked this effect in all cases. On the other hand, zinc IX protoporphyrin did not modify NO-mediated reaction caused by injection of L-arginine, while hemin compensated (though not completely) vasoconstriction induced by NO synthase blocker L-NAME. In contrast to NO, the effect of CO on blood vessels was not so rapid and potent, but more lasting. Other targets for CO were arteries with well-developed muscular tunic, while targets for NO were small vessels. The vasomotor effects of both gas transmitters were more pronounced in young animals.

Mitochondria and carbon monoxide: cytoprotection and control of cell metabolism - a role for Ca(2+) ?

Carbon monoxide (CO) is an endogenously produced gasotransmitter with important biological functions: anti-inflammation, anti-apoptosis, vasomodulation and cell metabolism modulation. The most recognized cellular target for CO is the mitochondria. Physiological concentrations of CO generate mitochondrial reactive oxygen species (ROS), which are signalling molecules for CO-induced pathways. Indeed, small amounts of ROS promote cytoprotection by a preconditioning effect. Furthermore, CO prevents cell death by limiting mitochondrial membrane permeabilization, which inhibits the release of pro-apoptotic factors into the cytosol; both events are ROS dependent. CO also increases the ability of mitochondria to take up Ca(2+) . Mitochondrial metabolism is modulated by CO, namely by increasing TCA cycle rate, oxidative phosphorylation and mitochondrial biogenesis, which, in turn, increases ATP production. CO's modulation of metabolism might be important for cellular response to diseases, namely cancer and ischaemic diseases. Finally, another cytoprotective role of CO involves the control of Ca(2+) channels. By limiting the activity of T-type and L-type Ca(2+) channels, CO prevents excitotoxicity-induced cell death and modulates cell proliferation. Several questions concerning Ca(2+) signalling, mitochondria and CO can be asked, for instance whether CO modulation of cell metabolism would be dependent on the mitochondrial Ca(2+) uptake capacity, since small amounts of Ca(2+) can increase mitochondrial metabolism. Whether CO controls Ca(2+) communication between mitochondria and endoplasmic reticulum is another open field of research. In summary, CO emerges as a key gasotransmitter in the control of several cellular functions of mitochondria: metabolism, cell death and Ca(2+) signalling.

The emerging role of gasotransmitters in the pathogenesis of tuberculosis.

Mycobacterium tuberculosis (Mtb) is a facultative intracellular pathogen and the second largest contributor to global mortality caused by an infectious agent after HIV. In infected host cells, Mtb is faced with a harsh intracellular environment including hypoxia and the release of nitric oxide (NO) and carbon monoxide (CO) by immune cells. Hypoxia, NO and CO induce a state of in vitro dormancy where Mtb senses these gases via the DosS and DosT heme sensor kinase proteins, which in turn induce a set of ∼47 genes, known as the Mtb Dos dormancy regulon. On the contrary, both iNOS and HO-1, which produce NO and CO, respectively, have been shown to be important against mycobacterial disease progression. In this review, we discuss the impact of O2, NO and CO on Mtb physiology and in host responses to Mtb infection as well as the potential role of another major endogenous gas, hydrogen sulfide (H2S), in Mtb pathogenesis.

[Relaxation mechanism of smooth muscle cells and its relationship with penile erection].

The contractile and diastolic function of smooth muscle cells (SMCs) is closely related to penile erection and erectile dysfunction (ED). In addition to nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), sulfur dioxide (SO2), estrogen receptor (ER), P2Y receptor, perivascular tissue (PVT), and calcium activated potassium channel (Kca) are found to be involved in the relaxation of SMCs. This review updates the mechanisms of the relaxation of SMCs and its relationship with ED.

Effects of polluted air on cardiovascular and hematological parameters after progressive maximal aerobic exercise.

PURPOSE: Exercising or doing physical activity in polluted air could expose a person to the adverse health effects of air pollution. This study aimed to compare the cardiovascular and hematologic indices following an incremental exercise test (shuttle run) under clean versus polluted air conditions. METHODS: Nineteen male athletes aged 21-27 years were assigned to either a trained athletes group (TA, n = 10) or a complete training cessation/detrained athletes group (DA, n = 9) at least 3-4 months after their competitive season. All participants performed the multi-stage shuttle run test on two separate days in either polluted air (37.4 carbon monoxide part per million) or clean air (2.5 carbon monoxide part per million) condition. RESULTS: When compared to the clean air environment, progressive incremental exercise in polluted air condition significantly (p < .05) decreased maximal oxygen uptake (VO2max), red blood cell count, and hematocrit for both TA and DA groups. Meanwhile, the participants' mean corpuscular hemoglobin, mean red blood cell volume, white blood cells, and platelets in these two groups increased significantly (p < .05) when they were exercised in the polluted air ambiance. Maximal heart rate and heart rate recovery showed significant (p = .04) increases only in the DA group. However, hemoglobin concentration remained unchanged in both groups. CONCLUSION: Acute exposure to high concentrations of pollutants during exercise resulted in decline in cardiovascular functions and hematological parameters in healthy athletes.

Heme Oxygenase-1 Influences Apoptosis via CO-mediated Inhibition of K+ Channels.

Hypoxic/ischemic episodes can trigger oxidative stress-mediated loss of central neurons via apoptosis, and low pO2 is also a feature of the tumor microenvironment, where cancer cells are particularly resistant to apoptosis. In the CNS, ischemic insult increases expression of the CO-generating enzyme heme oxygenase-1 (HO-1), which is commonly constitutively active in cancer cells. It has been proposed that apoptosis can be regulated by the trafficking and activity of K(+) channels, particularly Kv2.1. We have explored the idea that HO-1 may influence apoptosis via regulation of Kv2.1. Overexpression of Kv2.1 in HEK293 cells increased their vulnerability to oxidant-induced apoptosis. CO (applied as the donor CORM-2) protected cells against apoptosis and inhibited Kv2.1 channels. Similarly in hippocampal neurones, CO selectively inhibited Kv2.1 and protected neurones against oxidant-induced apoptosis. In medulloblastoma sections we identified constitutive expression of HO-1 and Kv2.1, and in the medulloblastoma-derived cell line DAOY, hypoxic HO-1 induction or exposure to CO protected cells against apoptosis, and also selectively inhibited Kv2.1 channels expressed in these cells. These studies are consistent with a central role for Kv2.1 in apoptosis in both central neurones and cancer cells. They also suggest that HO-1 expression can strongly influence apoptosis via CO-mediated regulation of Kv2.1 activity.

[Combined pulmonary fibrosis and emphysema syndrome]. / Sindrom plucne fibroze udruzene s emfizemom.

CPFE-combined pulmonary fibrosis and emphysema is a new term for a syndrome whose main characteristic is fibrosis in lower pulmonary lobes with simultaneous emphysema in upper pulmonary lobes. CPFE patients have well preserved pulmonary test values for unexpectedly long period, but extremely lowered carbon monoxide diffusion capacity and significant arterial hypertension. All CPFE studies indicate that CPFE occurs predominately in older male population. Smoking is considered main cause in developing CPFE. Reduced survival rate is linked with arterial hypertension extent, and mortality rate is greater than that for patients with isolated pulmonary fibrosis or emphysema. This study is focused on characteristics of twelve CPFE patients. This paper describes cases of 12 patients with the syndrome of pulmonary fibrosis associated with emphysema. All patients were male, mean age of 68 years. At the certain period of life they all were smokers, but most of them were also exposed to air pollution due to their profession. Shortness of breath on exertion was present in all patients. All patients had neat pulmonary function tests with significantly reduced diffusing capacity for carbon mon- oxide (average 39%). Pulmonary arterial hypertension (PAH) averaged 56 mmHg (range 25-75 mmHg) was present in 75% of patients. Four patients died during the period of four months, of which three patients had PAH greater than 70 mmHg. The fourth patient died of lung cancer.

Advances in the pathophysiology of pre-eclampsia and related podocyte injury.

Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions.