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High carbon monoxide (CO) concentrations can elicit adverse health effects. We assessed CO concentrations at filling stations and determined carboxyhemoglobin (%COHb) levels and health problems reported by filling station attendants (FSAs) via questionnaires. This cross-sectional design studied 20 filling stations from Ibadan North Local Government, Nigeria. Outdoor CO concentrations (ppm) were measured for 8 weeks in August-September 2015 from 8:00-10:00 a.m. and 12:00-2:00 p.m., and %COHb levels were measured among 100 FSAs. Data collected were analyzed using Student's t-test and analysis of variation (p = .05) and compared with relevant guideline limits. Mean CO concentrations in morning (15.4 [+ or -] 2.1 ppm) and afternoon (11.6 [+ or -] 1.4 ppm) were higher (p < .01) than the World Health Organization (WHO) guideline of 9.0 ppm. Mean %COHb for FSAs (11.1 [+ or -] 2.6) was significantly higher (p < .01) than the WHO guideline of 2.5%. Among respondents, 13.4% of FSAs vomited and 14.9% of FSAs experienced nausea. FSAs need personal protective equipment and filling stations should modernize pump delivery systems to minimize exposures., Introduction Carbon monoxide (CO) is a widely distributed air pollutant. It is a colorless, odorless, and tasteless gas that is poorly soluble in water. CO has a high affinity to [...]

Author(s): Yoon Kyung Choi (corresponding author) [1, 2]; Takakuni Maki [1, 2]; Emiri T Mandeville [1, 2]; Seong-Ho Koh [1, 2, 3]; Kazuhide Hayakawa [1, 2]; Ken Arai [1, 2]; [...]

Ultrafine particles (UFPs) are ubiquitous in urban air and have been recognized as a risk to human health. The aim of this study was to measure the relationships among ultrafine particles and other ambient air pollutants and meteorological factors in the Tampa Bay Area. This study measured continuous UFPs, black carbon, oxides of nitrogen (N[O.sub.x]), nitrogen dioxide (N[O.sub.2]), nitric oxide (NO), carbon monoxide (CO), ozone ([O.sub.3]), sulfur dioxide (S[O.sub.2]), particulate matter having an aerodynamic diameter of 10 microns or less ([PM.sub.10]), relative humidity, wind speed, and ambient temperature during January to March 2014. Moreover, the study compared the relationship between UFPs and various co-pollutants daily, including during morning rush hour periods. This study found a moderate correlation among UFPs and black carbon, N[O.sub.x], N[O.sub.2], and NO during hourly continuous measurements and rush hour periods, and a low level of correlation among UFPs and CO, [O.sub.3], S[O.sub.2], [PM.sub.10], relative humidity, wind speed, and ambient temperature. This study indicates that co-pollutants should not be used as a surrogate to assess the human health risk from ultrafine particles exposure., Introduction Ultrafine particles (UFPs) are defined as particles that have a size ≤ 100 nanometers in diameter ([less than or equal to] 100 nm or ≤ 0.1 pm). They are [...]

On an evening in December 2014, a teenager passed out after finishing a hockey game in Lake Delton, Wisconsin. Other players and spectators reported headaches, nausea, vomiting, and dizziness. Local [...]

ARTICLE INFO Keywords: Quercetin Heme oxygenase-1 (H0-1) CYP2E1 Carbon monoxide (CO) Ethanol ABSTRACT Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (H0-1) induction and carbon monoxide [...]

In the study described in this article, the authors' objective was to measure particles ≤2.5 um in aerodynamic diameter ([PM.sub.2.5]) and carbon monoxide (CO) in outdoor waiting areas and patios of restaurants and bars in downtown Athens, Georgia, where indoor smoking is banned. The authors also wanted to investigate whether the measured concentrations are directly associated with the number of cigarettes lit in these settings. Real-time [PM.sub.2.5] and CO were monitored on four summer weekend afternoons/evenings in outdoor waiting areas or patios at five locations in Athens. In addition, smokers and pedestrians present or passing and motorized vehicles passing each sampling location were counted. [PM.sub.2.5] levels were significantly higher than levels at the control location (all p-values > .001). Carbon monoxide levels outside the restaurant and bar sites did not differ significantly from the control. The results of the authors' study indicate that (1) secondhand smoke (SHS) leads to significant increases in [PM.sub.2.5] outside of restaurants and bars; and (2) although CO can be used as a proxy for SHS in these outdoor environments, its levels remain relatively low., Introduction Secondhand smoke (SHS) is the mixture of smoke given off at the burning end (side-stream smoke) of tobacco products and the mainstream smoke exhaled by smokers (U.S. Department of [...]

Carbon monoxide (CO) confers anti-inflammatory protection in rodent models of lung injury when applied at low concentration. Translation of these findings to clinical therapies for pulmonary inflammation requires validation in higher mammals. We have evaluated the efficacy of inhaled CO in reducing LPS-induced lung inflammation in cynomolgus macaques. LPS inhalation resulted in profound neutrophil influx and moderate increases in airway lymphocytes, which returned to baseline levels within 2 wk following exposure. CO exposure (500 ppm, 6 h) following LPS inhalation decreased TNF-[alpha] release in bronchoalveolar lavage fluid but did not affect IL-6 or IL-8 release. Lower concentrations of CO (250 ppm, 6 h) did not reduce pulmonary neutrophilia. Pretreatment with budesonide, a currently used inhaled corticosteroid, decreased LPS-induced expression of TNF-[alpha], IL-6, and IL-8, and reduced LPS-induced neutrophilia by ~84%. In comparison, CO inhalation (500 ppm, for 6 h after LPS exposure) reduced neutrophilia by ~67%. Thus, inhaled CO was nearly as efficacious as pretreatment with an inhaled corticosteroid at reducing airway neutrophil influx in cynomolgus macaques. However, the therapeutic efficacy of CO required relatively high doses (500 ppm) that resulted in high carboxyhemoglobin (COHb) levels (>30%). Lower CO concentrations (250 ppm), associated with antiinflammatory protection in rodents, were ineffective in cynomolgus macaques and also yielded relatively high COHb levels. These studies highlight the complexity of interspecies variation of dose-response relationships of CO to COHb levels and to the anti-inflammatory functions of CO. The findings of this study warrant further investigations for assessing the therapeutic application of CO in nonhuman primate models of tissue injury and in human diseases. The study also suggests that akin to many new therapies in human diseases, the translation of CO therapy to human disease will require additional extensive and rigorous proof-of-concept studies in humans in the future. lipopolysaccharide doi: 10.1152/ajplung.00366.2009.

Carbon monoxide (CO) causes cerebral arteriolar dilation in newborn pigs by the activation of large-conductance [Ca.sup.2+]-activated [K.sup.+] channels. In adult rat cerebral and skeletal muscle arterioles, CO has been reported to produce constriction caused by the inhibition of nitric oxide (NO) synthase (NOS). We hypothesized that, in contrast to dilation to acute CO, more prolonged exposure of newborn cerebral arterioles to elevated CO produces constriction by reducing NO. In piglets with closed cranial windows, pial arteriolar responses to isoproterenol ([10.sup.-6] M), sodium nitroprusside (SNP; [10.sup.-7] and 3 x [10.sup.-7] M), and L-arginine ethyl ester (L-Arg; [10.sup.-5] and [10.sup.-4] M) were determined before and after 2 h of treatment with CO. CO ([10.sup.-7] M) caused transient dilation and had no further effects. CO (2 x [10.sup.-7] and [10.sup.-6] M) initially caused vasodilation, but over the 2-h exposure, pial arterioles constricted and removal of the CO caused dilation. Exposure to elevated CO (2 h) did not alter dilation to SNP or isoproterenol. Conversely, the NOS substrate L-Arg caused dilation before CO that was progressively lost over 90 min of elevated CO. If NO was held constant, CO caused dilation that was sustained for 2 h. We conclude that in neonates, cerebral arteriole responses to CO are biphasic: dilation to acute elevation with subsequent constriction from NOS inhibition after more prolonged exposure. As a result, short episodic production of CO allows function as a dilator gasotransmitter, whereas prolonged elevation can reduce NO to elevate cerebrovascular tone. The interaction between heine oxygenase/CO and NOS/NO could form a negative feedback system in the control of cerebral vascular tone. nitric oxide; neonate doi: 10.1152/ajpheart.00258.2010.

Summary This article focuses on the causes, diagnosis and management of carbon monoxide poisoning. R describes assessment strategies and treatment options for the patient with potential carbon monoxide poisoning. Keywords [...]

Myocardial damages due to ischemia-reperfusion (I/R) are recognized to be the result of a complex interplay between genetic and environmental factors. Epidemiological studies suggested that, among environmental factors, carbon monoxide (CO) urban pollution can be linked to cardiac diseases and mortality. The aim of this work was to evaluate the impact of exposure to CO pollution on cardiac sensitivity to I/R. Regional myocardial I/R was performed on isolated perfused hearts from rats exposed for 4 wk to air enriched with CO (30-100 ppm). Functional variables, reperfusion ventricular arrhythmias (VA) and cellular damages (infarct size, lactate dehydrogenase release) were assessed. Sarcomere length shortening and [Ca2.sup.+] handling were evaluated in intact isolated cardiomyocytes during a cellular anoxia-reoxygenation protocol. The major results show that prolonged CO exposure worsens myocardial I/R injuries, resulting in increased severity of postischemic VA, impaired recovery of myocardial function, and increased infarct size (60 [+ or -] 5 vs. 33 [+ or -] 2% of ischemic zone). The aggravating effects of CO exposure on I/R could be explained by a reduced myocardial enzymatic antioxidant status (superoxide dismutase -45%; glutathione peroxidase -49%) associated with impaired intracellular [Ca2.sup.+] handling. In conclusion, our results are consistent with the idea that chronic CO pollution dramatically increases the severity of myocardial I/R injuries. environmental pollution; myocardial infarction; antioxidant status doi: 10.1152/ajpheart.01194.2009.

Cardiopulmonary bypass (CPB) is associated with significant postoperative morbidity, but its effects on the neuromuscular system are unclear. Recent studies indicate that even relatively short periods of mechanical ventilation result in significant neuromuscular effects. Carbon monoxide (CO) has gained recent attention as therapy to reduce the deleterious effects of CPB. We hypothesized that 1) CPB results in impaired neuromuscular transmission and reduced diaphragm force generation; and 2) CO treatment during CPB will mitigate these effects. In adult male Sprague-Dawley rats, diaphragm muscle-specific force and neuromuscular transmission properties were measured 90 min after weaning from normothermic CPB (1 h). During CPB, either low-dose inhaled CO (250 ppm) or air was administered. The short period of mechanical ventilation used in the present study (~3 h) did not adversely affect diaphragm muscle contractile properties or neuromuscular transmission. CPB elicited a significant decrease in isometric diaphragm muscle-specific force compared with time-matched, mechanically ventilated rats (~25% decline in both twitch and tetanic force). Diaphragm muscle fatigability to 40-Hz repetitive stimulation did not change significantly. Neuromuscular transmission failure during repetitive activation was 60 [+ or -] 2% in CPB animals compared with 76 [+ or -] 4% in mechanically ventilated rats (P < 0.05). CO treatment during CPB abrogated the neuromuscular effects of CPB, such that diaphragm isometric twitch force and neuromuscular transmission were no longer significantly different from mechanically ventilated rats. Thus, CPB has important detrimental effects on diaphragm muscle contractility and neuromuscular transmission that are largely mitigated by CO treatment. Further studies are needed to ascertain the underlying mechanisms of CPB-induced neuromuscular dysfunction and to establish the potential role of CO therapy. carbon monoxide; skeletal muscle; fatigue doi:10.1152/ajpregu.00737.2009

Carbon monoxide (CO) has anti-inflammatory properties. We previously reported that acute treatments with inhaled CO inhibit vascular inflammation and hypoxia-induced vasoocclusion in sickle cell disease mouse models. Therefore, we hypothesized that chronic CO inhalation would decrease vascular inflammation and organ pathology in a sickle cell disease mouse model. The treatment of sickle cell disease mice with 25 or 250 parts/million inhaled CO for 1 h/day, 3 days/wk for 8-10 wk significantly decreased the total mean white blood cell, neutrophil, and lymphocyte counts in peripheral blood. Eight weeks of 250 parts/million CO treatments reduced staining for myeloid and lymphoid markers in the bone marrow of sickle mice. Bone marrow from treated sickle mice exhibited a significant decrease in colony-forming unit granulocyte-macrophage during colony-forming cell assays. Anti-inflammatory signaling pathways phospho-Akt and phospho-p38 MAPK were markedly increased in CO-treated sickle livers. Importantly, CO-treated sickle mice had a significant reduction in liver parenchymal necrosis, reflecting the anti-inflammatory benefits of CO. We conclude that inhaled CO may be a beneficial anti-inflammatory therapy for sickle cell disease. inflammation; heme oxygenase doi: 10.1152/ajpheart.00327.2009

Given that the physiology of heine oxygenase-1 (HO-1) encompasses mitochondrial biogenesis, we tested the hypothesis that the HO-1 product, carbon monoxide (CO), activates mitochondrial biogenesis in skeletal muscle and enhances maximal oxygen uptake ([??].sub.2max]) in humans. In l0 healthy subjects, we biopsied the vastus lateralis and performed [??].sub.2max] tests followed by blinded randomization to air or CO breathing (1 h/day at 100 parts/million for 5 days), a contralateral muscle biopsy on day 5, and repeat [??].sub.2max] testing on day 8. Six independent subjects underwent CO breathing and two muscle biopsies without exercise testing. Molecular studies were performed by real-time RT-PCR, Western blot analysis, and immunochemistry. After [??].sub.2max] testing plus CO breathing, significant increases were found in mRNA levels for nuclear respiratory factor-1, peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha], mitochondrial transcription factor-A (Tfam), and DNA polymerase [gamma](Pol[gamma]) with no change in mitochondrial DNA (mtDNA) copy number or [??].sub.2max]. Levels of myosin heavy chain I and nuclear-encoded HO-1, superoxide dismutase-2, citrate synthase, mitofusin-1 and -2, and mitochondrial-encoded cytochrome oxidase subunit-I (COX-I) and ATPase-6 proteins increased significantly. None of these responses were reproduced by [??].sub.2max] testing alone, whereas CO alone increased Tfam and Pol[gamma] mRNA, and COX-I, ATPase-6, mitofusin-2, HO-1, and superoxide dismutase protein. These findings provide evidence linking the HO/CO response involved in mitochondrial biogenesis in rodents to skeletal muscle in humans through a set of responses involving regulation of the mtDNA transcriptosome and mitochondrial fusion proteins autonomously of changes in exercise capacity. heme oxygenase-1; superoxide dismutase-2; peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha]; nuclear respiratory factor-1; oxygen uptake

We recently reported that carbon monoxide (CO) has bactericidal activity. To understand its mode of action we analysed the gene expression changes occurring when Escherichia coli, grown aerobically and anaerobically, is treated with the CO-releasing molecule CORM-2 (tricarbonyldichlororuthenium(II) dimer). Microarray analysis shows that the E. coli CORM-2 response is multifaceted, with a high number of differentially regulated genes spread through several functional categories, namely genes involved in inorganic ion transport and metabolism, regulators, and genes implicated in post-translational modification, such as chaperones. CORM-2 has a higher impact in E. coli cells grown anaerobically, as judged by the repression of genes belonging to eight functional classes which are not seen in the response of aerobically CORM-2-treated cells. The biological relevance of the variations caused by CORM-2 was substantiated by studying the CORM-2 sensitivity of selected E. coli mutants. The results show that the deletion of redox-sensing regulators SoxS and OxyR increased the sensitivity to CORM-2 and suggest that while SoxS plays an important role in protection against CORM-2 under both growth conditions, OxyR seems to participate only in the aerobic CORM-2 response. Under anaerobic conditions, we found that the heat-shock proteins IbpA and IbpB contribute to CORM-2 defence since the deletion of these genes increases the sensitivity of the strain. The induction of several met genes and the hypersensitivity to CORM-2 of the [DELTA]metR, [DELTA]metl and [DELTA]metN mutant strains suggest that CO has effects on the methionine metabolism of E. coli CORM-2 also affects the transcription of several E. coli biofilm-related genes and increases biofilm formation in E. coli. In particular, the absence of tqsA or bhsA increases the resistance of E. coli to CORM-2, and deletion of tsqA leads to a strain that has lost its capacity to form biofilm upon treatment with CORM-2. In spite of the relatively stable nature of the CO molecule, our results show that CO is able to trigger a significant alteration in the transcriptome of E. coli which necessarily has effects in several key metabolic pathways.

Heme oxygenase (HO) represents the rate-limiting enzyme in the degradation of heine into carbon monoxide (CO), iron, and biliverdin. Recent evidence suggests that several of the beneficial properties of HO, may be linked to CO. The objectives of this study were to determine if low-dose inhaled CO reduces remote intestinal leukocyte recruitment, proinflammatory cytokine expression, and oxidative stress elicited by hindlimb ischemia-reperfusion (I/R). Male mice underwent 1 h of hindlimb ischemia, followed by 3 h of reperfusion. Throughout reperfusion, mice were exposed to AIR or AIR + CO (250 ppm). Following reperfusion, the distal ileum was exteriorized to assess the intestinal inflammatory response by quantifying leukocyte rolling and adhesion in submucosal postcapillary venules with the use of intravital microscopy. Ileum samples were also analyzed for proinflammatory cytokine expression [tumor necrosis factor (TNF)-[alpha] and interleukin (IL)-l[beta] and malondialdehyde (MDA) with the use of enzyme-linked immunosorbent assay and thiobarbituric acid reactive substances assays, respectively. I/R + AIR led to a significant decrease in leukocyte rolling velocity and a sevenfold increase in leukocyte adhesion. This was also accompanied by a significant 1.3-fold increase in ileum MDA and 2.3-fold increase in TNF-[alpha] expression. Treatment with AIR + CO led to a significant reduction in leukocyte recruitment and TNF-[alpha] expression elicited by I/R; however, MDA levels remained unchanged. Our data suggest that low-dose inhaled CO selectively attenuates the remote intestinal inflammatory response elicited by hindlimb I/R, yet does not provide protection against intestinal lipid peroxidation. CO may represent a novel anti-inflammatory therapeutic treatment to target remote organs following acute trauma and/or I/R injury. carbon monoxide; inflammation; ischemia-reperfusion; systemic inflammatory response syndrome

Carbon monoxide derived from heme oxygenase (HO) may participate in cerebrovascular regulation under specific circumstances. Previous work has shown that HO contributes to feline pial arteriolar dilation to acetylcholine after transfusion of a cell-free polymeric hemoglobin oxygen cartier. The role of constitutive HO2 in the pial arteriolar dilatory response to acetylcholine was determined by using 1) HO2-null mice (HO[2.sup.-/-]), 2) the HO inhibitor tin protoporphyrin IX (SnPPIX), and 3) 4,5,6,7tetrabromobenzotriazole (TBB), an inhibitor of case-in kinase-2 (CK2)-dependent phosphorylation of HO2. In anesthetized mice, superfusion of a cranial window with SnPPIX decreased arteriolar dilation produced by 10 [micro]M acetylcholine by 51%. After partial polymeric hemoglobin exchange transfusion, the acetylcholine response was normal but was reduced 72% by SnPPIX and 95% by TBB. In HO[2.sup.-/-] mice, the acetylcholine response was modestly reduced by 14% compared with control mice and was unaffected by SnPPIX. After hemoglobin transfusion in HO[2.sup.-/-] mice, acetylcholine responses were also unaffected by SnPPIX and TBB. In contrast, nitric oxide synthase inhibition completely blocked the acetylcholine responses in hemoglobin-transfused HO[2.sup.-/-] mice. We conclude 1) that HO2 activity partially contributes to acetylcholine-induced pial arteriolar dilation in mice, 2) that this contribution is augmented in the presence of a plasma-based hemoglobin polymer and appears to depend on a CK2 kinase mechanism, 3) that nitric oxide synthase activity rather than HO1 activity contributes to the acetylcholine reactivity in HO[2.sup.-/-] mice, and 4) that plasma-based polymeric hemoglobin does not scavenge all of the nitric oxide generated by cerebrovascular acetylcholine stimulation. blood substitutes; cerebral artery; cerebral circulation; carbon monoxide; endothelium-dependent dilation; nitric oxide

Byline: Roberta Foresti (1), Mohamed G. Bani-Hani (1), Roberto Motterlini (1) Abstract: As a by-product of heme catabolism by the heme oxygenase system, carbon monoxide (CO) has been neglected for many years, and only recently has its role as an essential signaling molecule been appreciated. In the past decade, the use of CO gas in pre-clinical experimental models of disease has produced some remarkable data indicating that its therapeutic delivery to mammals could alleviate inflammatory processes and cardiovascular disorders. However, the inherent toxic nature of CO cannot be ignored, knowing that inhalation of uncontrolled amounts of this gas can ultimately lead to serious systemic complications and neuronal derangements. From a clinical perspective, a key question is whether a safe and therapeutically effective threshold of CO can be reached locally in organs and tissues without delivering potentially toxic amounts through the lung. The advent of CO-releasing molecules (CO-RMs), a group of compounds capable of carrying and liberating controlled quantities of CO in cellular systems, appears a plausible alternative in the attempt to overcome the limitations of CO gas. Although in its infancy and far from being used for clinical applications, the CO-RMs technology is supported by very encouraging biological results and reflected by the chemical versatility of these compounds and their endless potential to be transformed into CO-based pharmaceuticals. Author Affiliation: (1) Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, HA1 3UJ, Harrow, Middlesex, UK Article History: Registration Date: 08/01/2008 Received Date: 14/06/2007 Accepted Date: 01/11/2007 Online Date: 20/02/2008 Article note: This article is discussed in the editorial available at: http://dx.doi.org/10.1007/s00134-008-1013-z.

Byline: Michael Bauer (1), Klaus Huse (2), Utz Settmacher (3), Ralf A. Claus (1) Abstract: Heme oxygenase (HO) breaks down heme, the iron-containing, oxygen-carrying constituent of red blood cells, yielding biliverdin, iron (II) ions, and carbon monoxide (CO). Among the isoenzymes cloned to date, only HO-1 can be induced by a panoply of stimuli linked by their ability to provoke oxidative stress. HO-1 induction protects against cell death in experimental models associated with ischemia/reperfusion or inflammation, making the gene a promising target for critical care medicine. Induction of HO-1 may confer protection by controlling intracellular levels of toxic heme, or by anti-inflammatory, anti-apoptotic, and blood flow-maintaining effects of its by-products biliverdin and CO. Although protective effects of upregulation of HO-1 have been reported for a variety of cells and tissues, evidence suggests that the protective action may be restricted to a rather narrow threshold of overexpression. In addition, there is substantial variation in gene expression depending on transcriptional control mechanisms such as a microsatellite length polymorphism. Genetic variability and the required use of cytotoxic inducers are hurdles for purposeful targeting of HO-1 gene expression in critical care, while administration of by-products of the pathway seems feasible at present. Author Affiliation: (1) Department of Anesthesiology and Intensive Care Medicine, Friedrich Schiller University Hospital, Erlanger Allee 101, 07740, Jena, Germany (2) Leibniz Institute for Age Research -- Fritz Lipmann Institute, Jena, Germany (3) Department of General, Visceral, and Vascular Surgery, Friedrich Schiller University Hospital, Jena, Germany Article History: Registration Date: 08/01/2008 Received Date: 27/03/2006 Accepted Date: 05/11/2007 Online Date: 20/02/2008 Article note: This article is discussed in the editorial available at: http://dx.doi.org/10.1007/s00134-008-1013-z.

Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heine oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of s-smooth muscle actin ([alpha]-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-[[beta].sub.1]-induced expression of [alpha]-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy. transforming growth factor-[[beta].sub.1]; obstructive nephropathy; MAPK; MKK3; HO-1

Background: Household air pollution from solid fuel burning is a leading contributor to disease burden globally. Fine particulate matter ([PM.sub.2.5]) is thought to be responsible for many of these health impacts. A co-pollutant, carbon monoxide (CO) has been widely used as a surrogate measure of [PM.sub.2.5] in studies of household air pollution. Objective: The goal was to evaluate the validity of exposure to CO as a surrogate of exposure to [PM.sub.2.5] in studies of household air pollution and the consistency of the [PM.sub.2.5]-CO relationship across different study settings and conditions. Methods: We conducted a systematic review of studies with exposure and/or cooking area [PM.sub.2.5] and CO measurements and assembled 2,048 [PM.sub.2.5] and CO measurements from a subset of studies (18 cooking area studies and 9 personal exposure studies) retained in the systematic review. We conducted pooled multivariate analyses of [PM.sub.2.5]-CO associations, evaluating fuels, urbanicity, season, study, and CO methods as covariates and effect modifiers. Results: We retained 61 of 70 studies for review, representing 27 countries. Reported [PM.sub.2.5]-CO correlations (r) were lower for personal exposure (range: 0.22-0.97; median = 0.57) than for cooking areas (range: 0.10-0.96; median = 0.71). In the pooled analyses of personal exposure and cooking area concentrations, the variation in ln(CO) explained 13% and 48% of the variation in ln([PM.sub.2.5]), respectively. Conclusions: Our results suggest that exposure to CO is not a consistently valid surrogate measure of exposure to [PM.sub.2.5]. Studies measuring CO exposure as a surrogate measure of PM exposure should conduct local validation studies for different stove/fuel types and seasons. https://doi.org/10.1289/EHP767, Introduction Over 2.8 billion people are exposed to household air pollution from cooking and heating with solid fuels, which include biomass (e.g., wood, crop residues, animal dung, charcoal) and coal [...]

OBJECTIVES: We investigated the short-term effects of carbon monoxide on total and cardiovascular mortality in 19 European cities participating in the APHEA-2 (Air Pollution and Health: A European Approach) project. METHODS: We examined the association using hierarchical models implemented in two stages. In the first stage, data from each city were analyzed separately, whereas in the second stage the city-specific air pollution estimates were regressed on city-specific covariates to obtain overall estimates and to explore sources of possible heterogeneity. We evaluated the sensitivity of our results by applying different degrees of smoothing for seasonality control in the city-specific analysis. RESULTS: We found significant associations of CO with total and cardiovascular mortality. A 1-mg/[m.sup.3] increase in the 2-day mean of CO levels was associated with a 1.20% [95% confidence interval (CI), 0.63-1.77%] increase in total deaths and a 1.25% (95% CI, 0.30-2.21%) increase in cardiovascular deaths. There was indication of confounding with black smoke and nitrogen dioxide, but the pollutant-adjusted effect of CO on mortality remained at least marginally statistically significant. The effect of CO on total and cardiovascular mortality was observed mainly in western and southern European cities and was larger when the standardized mortality rate was lower. CONCLUSIONS: The results of this large study are consistent with an independent effect of CO on mortality. The heterogeneity found in the effect estimates among cities may be explained partly by specific city characteristics. KEY WORDS: air pollution, carbon monoxide, heterogeneity, modeling, mortality. Environ Health Perspect 115:1578-1583 (2007). doi:10.1289/ehp.10375 available via http://dx.doi.org/ [Online 16 August 2007], Adverse short-term effects of air pollution on health have been documented in recent years (Katsouyanni et al. 2001; Pope et al. 1995; Samet et al. 2000; Schwartz and Dockery 1992; [...]

Addition of Pco (~350 Torr) to a normoxic medium ([Po.sub.2] of ~130 Torr) was used to investigate the relationship between carotid body (CB) sensory discharge and expression of hypoxia-inducible factor 1[alpha] (HIF-1[alpha]) in glomus cells. Afferent electrical activity measured for in vitro-perfused rat CB increased rapidly (1-2 s) with addition of high CO (Pco of ~350 Torr; [Po.sub.2] of ~130 Torr), and this increase was fully reversed by white light. At submaximal light intensities, the extent of reversal was much greater for monochromatic light at 430 and 590 nm than for light at 450, 550, and 610 nm. This wavelength dependence is consistent with the action spectrum of the CO compound of mitochondrial cytochrome [a.sub.3]. Interestingly, when isolated glomus cells cultured for 45 min in the presence of high CO (Pco of ~350 Torr; [Po.sub.2] of ~130 Torr) in the dark, the levels of HIF-1[alpha], which turn over slowly (many minutes), increased. This increase was not observed if the cells were illuminated with white light during the incubation. Monochromatic light at 430+ and 590-nm light was much more effective than that at 450, 550, and 610 nm in blocking the CO-induced increase in HIF-1[alpha], as was the case for chemoreceptor discharge. Although the changes in HIF-1[alpha] take minutes and those for CB neural activity occur in 1-2 s, the similar responses to CO and light suggest that the oxygen sensor is the same (mitochondrial cytochrome [a.sub.3]). carbon monoxide; carotid body; cytochrome [a.sub.3]; hypoxia-inducible factor 1[alpha]; mitochondria; sensory discharge

We aimed to investigate the toxicity of carbon monoxide (CO) in rats with right ventricle (RV) remodeling induced by hypoxic pulmonary hypertension (PHT). A group of Wistar rats was exposed to 3-wk hypobaric hypoxia (H). A second group was exposed to 50 ppm CO for 1 wk (CO). A third group was exposed to chronic hypoxia including 50 ppm CO during the third week (H+CO). These groups were compared with controls. RV and left ventricle (LV) functions were assessed by echocardiography and transparietal catheterization. Ventricular perfusion was estimated with the fluorescent microsphere method. Results were confirmed by histology. PHT induced RV hypertrophy and function enhancement. In the H group, RV shortening fraction (RVSF; 71 [+ ot -] 12% vs. 41 [+ or -] 2%) and RV end-systolic pressure (RVESP; 54 [+ or -] 6 vs. 19 [+ or -] 2 mrnHg) were increased compared with controls. Moreover, myocardial perfusion was increased in the RV (36 [+ or -] 2% vs. 22 [+ or -] 2%) and decreased in the LV (64 [+ or -] 3% vs. 78 [+ or -] 2%). In the H+CO group, RVSF (45 [+ or -] 3% vs. 71 [+ or -] 12%) and RVESP (38 [+ or -] 3 vs. 54 [+ or -] 6 mmHg) were decreased compared with the H group. RV perfusion was decreased in the H+CO group compared with the H group (21 [+ or -] 5% vs. 36 [+ or -] 2%), and LV perfusion was increased (79 [+ or -] 5% vs. 64 [+ or -] 3%). PHT and RV hypertrophy were still present in the H+CO group, and fibroses localized in the RV were detected. Similar lesions were observed in an additional group exposed simultaneously to hypoxia and 50 ppm CO over 3 wk. We demonstrated that rats with established PHT were more sensitive to CO, which dramatically alters the RV adaptive response to PHT, leading to ischemic lesions. right ventricle remodeling; right ventricle perfusion

The most salient feature of carbon monoxide (CO)-mediated cytoprotection is the suppressiOn of inflammation and cell death. One of the important cellular targets of CO is the macrophage (m[PHI]). Many studies have shown that exposure of m[PHI] to CO results in the generation of an antiinflammatory phenotype; however, these reports have ignored the effect of CO alone on the cell before stimulation. Most investigations have focused on the actions of CO in modulating the response to noxious stimuli. We demonstrate here that exposure of m[PHI] to CO results in a significant and transient burst of reactive oxygen species (ROS) arising from the mitochondria (mitochondria-deficient m[PHI] do not respond to CO to produce ROS). The ROS promote rapid activation and stabilization of the transcription factor hypoxia-lnducible factor 1[alpha] (HIF-1[alpha]), which regulates expression of genes involved in inflammation, metabolism, and cell survival. The increase in HIF-1[alpha] expression induced by CO results in regulated expression of TGF-[beta], a potent antiinflammatory cytokine. CO-induced HIF-1[alpha] and TGF-[beta] expression are necessary to prevent anoxia/reoxygenation-induced apoptosis in m[PHI]. Furthermore, blockade of HIF-1[alpha] using RNA interference and HIF-1[alpha]-cre-lox m[PHI] resulted in a loss of TGF-[beta] expression and CO-induced protection. A similar mechanism of CO-induced protection was operational in vivo to protect against lung ischemia-reperfusion injury. Taken together, we conclude that CO conditions the m[PHI] via a HIF-1[alpha] and TGF-[beta]-dependent mechanism and we elucidate the earliest events in m[PHI] signaling that lead to and preserve cellular homeostasis at the site of injury. ischemia reperfusion | macrophage | heme oxygenase-1

Exogenous bilirubin (BR) substitutes for the protective effects of heme oxygenase (HO) in several organ systems. Our objective was to investigate the effects of exogenous BR in an in vivo model of ischemia-reperfusion injury (IRI) in the rat kidney. Four groups of male Sprague-Dawley rats were anesthetized using isoflurane in oxygen and treated with 1) 5 mg/kg intravenous (iv) BR, 1 h before ischemia and 6-h reperfusion; 2) vehicle 1 h before ischemia and 6-h reperfusion; 3) 20 mg/kg iv BR, 1 h before and during ischemia; and 4) vehicle 1 h before and during ischemia. Bilateral renal clamping (30 min) was followed by 6-h reperfusion. Infusion of 5 mg/kg iv BR achieved target levels in the serum at 6 h postischemia (31 [+ or -] 9 [micro]mol/l). Infusion of 20 mg/kg BR reached 50 [+ or -] 22 [micro]mol/1 at the end of ischemia, and a significant improvement was seen in serum creatinine at 6 h (1.07 [+ or -] 28 vs. 1.38 [+ or -] 0.18 mg/dl, P = 0.043). Glomerular filtration rate, estimated renal plasma flow, fractional excretion of electrolytes, and renal vascular resistance were not significantly improved in BR-treated groups. Histological grading demonstrated a trend toward preservation of cortical proximal tubules in rats receiving 20 mg/kg iv BR compared with control; however, neither BR dose provided protection against injury to the renal medulla. At the doses administered, iv BR did not provide complete protection against IRI in vivo. Combined supplementation of both BR and carbon monoxide may be required to preserve renal blood flow and adequately substitute for the protective effects of HO in vivo. heme oxygenase; carbon monoxide; biliverdin

Heme oxygenase-1 (HO-1, encoded by HMOX1) dampens inflammatory reactions via the catabolism of heme into CO, Fe, and biliverdin. We report that expression of HO-1 dictates the pathologic outcome of [...]

The gaseous compound carbon monoxide (CO) has been identified as an important endogenous biological messenger in brain and is a major component in regulation of celehrovascular circulation in newborns. CO is produced endogenously by catabolism of heme to CO, free iron, and biliverdin during enzymatic degradation of heme by heme oxygenase (HO). The present study was designed to test the hypothesis that endogenously produced CO contributes to hypotension-induced vasodilation of cerebral arterioles. Experiments used anesthetized piglets with implanted, closed cranial windows. Topical application of the HO substrate heme-L-lysinate caused dilation of pial arterioles that was blocked by a metal porphyrin inhibitor of HO, chromium mesoporphyrin (CrMP). In normotensive piglets (arterial pressure 64 [+ or -] 4 mmHg), CrMP did not cause vasoconstriction of pial arterioles but rather a transient dilation. Hypotension (50% of basal blood pressure) increased cerebral CO production and dilated pial arterioles from 66 [+ or -] 2 to 92 [+ or -] 7 [micro]m. In hypotensive piglets, topical CrMP or intravenous tin protoporphyrin decreased cerebral CO production and produced pial arteriolar constriction to normotensive diameters. In additional experiments, because prostacyclin and nitric oxide (NO) are also key dilators that can contribute to cerebrovascular dilation, we held their levels constant. NO/prostacyclin clamp was accomplished with continuous, simultaneous application of indomethacin, [N.sup.[omega]]-nitro-L-arginine, and minimal dilatory concentrations of iloprost and sodium nitroprusside. With constant NO and prostacyclin, the transient dilator and prolonged constrictor responses to CrMP of normotensive and hypotensive piglets, respectively, were the same as when NO and prostaglandins were not held constant. These data suggest that endogenously produced CO contributes to cerebrovascular dilation in response to reduced perfusion pressure. heme oxygenase; autoregulation; pial arterioles; newborn

Nitric oxide (NO) has been implicated in mediation of cerebral vasodilation during neuronal activation and, specifically, in pharmacological activation of N-methyl-D-aspartate (NMDA) and kainate receptors. Possible mediators of cerebral vasodilation to a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) have not been well studied in mature brain, although heme oxygenase (HO) activity has been implicated in newborn pigs. In anesthetized rats, 5 min of topical superfusion of 30 and 100 [micro]M AMPA on the cortical surface through a closed cranial window resulted in increases in pial arteriolar diameter. The dilatory response to AMPA was not inhibited by superfusion of an NO synthase inhibitor, a cyclooxygenase-2 inhibitor, or a cytochrome P-450 epoxygenase inhibitor, all of which have been shown to inhibit the cortical blood flow response to sensory activation. However, the 48 [+ or -] 13% dilation to 100 [micro]M AMPA was attenuated 56-71% by superfusion of the adenosine [A.sub.2A] receptor antagonist ZM-241385, the [A.sub.2B] receptor antagonist alloxazine, and the HO inhibitor chromium mesoporphyrin. Combination of the latter three inhibitors did not attenuate the dilator response more than the individual inhibitors, whereas an AMPA receptor antagonist fully blocked the vasodilation to AMPA. These results indicate that cortical pial arteriolar dilation to AMPA does not require activation of NO synthase, cyclooxygenase-2, or cytochrome P-450 epoxygenase but does depend on activation of adenosine [A.sub.2A] and [A.sub.2B] receptors. In addition, CO derived from HO appears to play a role in the vascular response to AMPA receptor activation in mature brain by a mechanism that is not additive with that of adenosine receptor activation. carbon monoxide; cerebral circulation; cyclooxygenase; epoxygenase; neurovascular coupling; nitric oxide doi:10.1152/ajpregu.00757.2005

Chronic allograft nephropathy (CAN) is the primary cause for late kidney allograft loss. Carbon monoxide (CO), a product of heme metabolism by heine oxygenases, is known to impart protection against various stresses. We hypothesized that CO could minimize the chronic fibroinflammatory process and protect kidney allografts from CAN. Lewis kidney grafts were orthotopically transplanted into binephrectomized Brown-Norway rats under short-course tacrolimus. Recipients were maintained in room air or exposed to CO at 20 parts/million for 30 days after transplant. Efficacy of inhaled CO was studied at day 30 and day 80. Isografts maintained normal kidney function throughout the experiment with creatinine clearance of ~1.5 ml/min. Renal allograft function in air controls progressively deteriorated, and creatinine clearance declined to 0.2 [+ or -] 0.1 ml/min by day 80 with substantial proteinuria. CO-treated animals had significantly better creatinine clearance (1.3 [+ or -]0.2 ml/min) with minimal proteinuria. Histological examination revealed the development of progressive CAN in air-exposed grafts, whereas CO-treated grafts had minimal tubular atrophy and interstitial fibrosis, with negligible collagen IV deposition. In vitro analyses revealed that CO-treated recipients had significantly less T cell proliferation against donor peptides via the indirect allorecognition pathway and less anti-donor IgG antibodies compared with air controls. Intragraft mRNA levels for chemokines (regulated on activation normal T cell expressed and secreted, macrophage inflammatory protein-1[alpha], chemokine receptors (CCR1, CXCR3, CXCR5), IL-2, and intercellular adhesion molecule-1 were significantly decreased in CO-treated than in air-treated allografts. Furthermore, reduction of blood flow in air-treated allografts was prevented with CO. In conclusion, inhaled CO at a low concentration efficiently abrogates chronic fibroinflammatory changes associated with CAN and improves long-term renal allograft function. kidney transplantation; cytoprotection; anti-inflammatory effect