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Efficacy and Safety of Inhaled Carbon Monoxide during Pulmonary Inflammation in Mice  [PDF]
Michael R. Wilson,Kieran P. O'Dea,Anthony D. Dorr,Hirotoshi Yamamoto,Michael E. Goddard,Masao Takata
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011565
Abstract: Pulmonary inflammation is a major contributor to morbidity in a variety of respiratory disorders, but treatment options are limited. Here we investigate the efficacy, safety and mechanism of action of low dose inhaled carbon monoxide (CO) using a mouse model of lipopolysaccharide (LPS)-induced pulmonary inflammation.
Does carbon monoxide treatment alter cytokine levels after endotoxin infusion in pigs? A randomized controlled study
Anna-Maja ?berg, Pernilla Abrahamsson, G?ran Johansson, Michael Haney, Ola Wins?, Jan Larsson
Journal of Inflammation , 2008, DOI: 10.1186/1476-9255-5-13
Abstract: Effects of CO administration on cytokine (TNF-alpha, IL-6, IL-1beta and IL-10) release were investigated in a porcine model in which a systemic inflammatory response syndrome was induced by endotoxin infusion. Endotoxin was infused in 20 anaesthetized and normoventilated pigs. Ten animals were targeted with inhaled CO to maintain 5% COHb, and 10 animals were controls.In the control group, mean pulmonary artery pressure increased from a baseline value of 17 mmHg (mean, n = 10) to 42 mmHg (mean, n = 10) following 1 hour of endotoxin infusion. Similar mean pulmonary artery pressure values were found in animals exposed to carbon monoxide. Plasma levels of all of the measured cytokines increased in response to the endotoxin infusion. The largest increase was observed in TNF-alpha, which peaked after 1.5 hours at 9398 pg/ml in the control group and at 13395 pg/ml in the carbon monoxide-exposed group. A similar peak was found for IL-10 while the IL-6 concentration was maximal after 2.5 hours. IL-1beta concentrations increased continuously during the experiment. There were no significant differences between carbon monoxide-exposed animals and controls in any of the measured cytokines.Our conclusion is that 5% COHb does not modify the cytokine response following endotoxin infusion in pigs.Carbon monoxide (CO) is recognized as a toxic gas in humans, originating from tobacco smoke, car exhaust and fire. CO bound to haemoglobin (Hb) can lead to injury related to impaired oxygen delivery, since the affinity of Hb for CO is much greater than for oxygen. CO also interferes with cellular respiration through the electron transport chain by inhibition of cytochrome c oxidase. However, some studies suggest that CO also has positive biological effects such as a vasodilative action [1,2]. Many in vitro studies, as well as studies in rodents postulate anti-inflammatory effects of CO [3-7]. A conflicting lack of effect of CO was found in humans after endotoxin exposure, where no protectiv
Postconditioning with Inhaled Carbon Monoxide Counteracts Apoptosis and Neuroinflammation in the Ischemic Rat Retina  [PDF]
Nils Schallner, Matthias Fuchs, Christian I. Schwer, Torsten Loop, Hartmut Buerkle, Wolf Alexander Lagrèze, Christian van Oterendorp, Julia Biermann, Ulrich Goebel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046479
Abstract: Purpose Ischemia and reperfusion injury (I/R) of neuronal structures and organs is associated with increased morbidity and mortality due to neuronal cell death. We hypothesized that inhalation of carbon monoxide (CO) after I/R injury (‘postconditioning’) would protect retinal ganglion cells (RGC). Methods Retinal I/R injury was performed in Sprague-Dawley rats (n = 8) by increasing ocular pressure (120 mmHg, 1 h). Rats inhaled room air or CO (250 ppm) for 1 h immediately following ischemia or with 1.5 and 3 h latency. Retinal tissue was harvested to analyze Bcl-2, Bax, Caspase-3, HO-1 expression and phosphorylation of the nuclear transcription factor (NF)-κB, p38 and ERK-1/2 MAPK. NF-κB activation was determined and inhibition of ERK-1/2 was performed using PD98059 (2 mg/kg). Densities of fluorogold prelabeled RGC were analyzed 7 days after injury. Microglia, macrophage and Müller cell activation and proliferation were evaluated by Iba-1, GFAP and Ki-67 staining. Results Inhalation of CO after I/R inhibited Bax and Caspase-3 expression (Bax: 1.9±0.3 vs. 1.4±0.2, p = 0.028; caspase-3: 2.0±0.2 vs. 1.5±0.1, p = 0.007; mean±S.D., fold induction at 12 h), while expression of Bcl-2 was induced (1.2±0.2 vs. 1.6±0.2, p = 0.001; mean±S.D., fold induction at 12 h). CO postconditioning suppressed retinal p38 phosphorylation (p = 0.023 at 24 h) and induced the phosphorylation of ERK-1/2 (p<0.001 at 24 h). CO postconditioning inhibited the expression of HO-1. The activation of NF-κB, microglia and Müller cells was potently inhibited by CO as well as immigration of proliferative microglia and macrophages into the retina. CO protected I/R-injured RGC with a therapeutic window at least up to 3 h (n = 8; RGC/mm2; mean±S.D.: 1255±327 I/R only vs. 1956±157 immediate CO treatment, vs. 1830±109 1.5 h time lag and vs. 1626±122 3 h time lag; p<0.001). Inhibition of ERK-1/2 did not counteract the CO effects (RGC/mm2: 1956±157 vs. 1931±124, mean±S.D., p = 0.799). Conclusion Inhaled CO, administered after retinal ischemic injury, protects RGC through its strong anti-apoptotic and anti-inflammatory effects.
Possible contribution of endogenous carbon monoxide to the development of allergic rhinitis in guinea pigs
Yu Shaoqing, Zhang Ruxin, Chen Yinjian, Chen Jianqiu, Zhu Chunsheng, Tang Jiangfeng, Li Genhong
Journal of Inflammation , 2008, DOI: 10.1186/1476-9255-5-23
Abstract: AR guinea pig model was established by nasal ovalbumin sensitization. Twenty-four AR guinea pigs were divided into four groups, 6 in each: Saline control group, AR sensitized group, Hemin treated group, and Zinc protoporphyrin (ZnPP) treated group. The frequency of sneezing and nose rubbing was recorded. Leukocyte infiltration in nasal lavage fluid, serum IgE level and plasma CO were measured. Expression of heme oxygenase-1 (HO-1) mRNA in nasal mucosa was determined by real time RT-PCR, and expression of HO-1 protein was detected by immunohistochemistry.The frequency of sneezing and nose rubbing, leukocyte infiltration, serum IgE, plasma CO, and HO-1 mRNA levels in sensitized guinea pigs were higher than those of control (P < 0.05). Except for serum IgE level, all above parameters were even higher (P < 0.05) when treated with Hemin, a heme oxygenase-1 inducer; but significantly decreased (P < 0.05) when treated with ZnPP, a heme oxygenase inhibitor. Immunohistochemical results showed that positive staining of HO-1 was present in the lamina of mucosa of sensitized guinea pigs, and there was an increase of HO-1 immunoreactivity with Hemin administration (P < 0.05) and a decrease with ZnPP treatment.The endogenous CO may take part in the inflammation process of AR and is positively correlated with expression of HO-1 in nasal mucosa. Endogenous CO plays a significant role in the pathogenesis of AR.Research on the role of the gas signal messenger such as nitric oxide (NO) and carbon monoxide (CO) in allergy medicine is a rapidly emerging field. Important roles of CO have been identified in many physiological and pathological processes relating to vasomotion, cell growth, even apoptosis [1,2]. CO is mainly produced by enzyme heme oxygenase (HO), which has been found to be expressed in almost all human tissues and organs. HO consists of three isozymes: HO-1, HO-2 and HO-3. HO-1, which is known as inducible form of heat shock protein 32 (HSP32), has been implicated in the r
Inhibitory effects of inhaled complex traditional Chinese medicine on early and late asthmatic responses induced by ovalbumin in sensitized guinea pigs
Hung-Chou Chang, Cheng-Chung Gong, Ji-Liang Chen, Oi-Tong Mak
BMC Complementary and Alternative Medicine , 2011, DOI: 10.1186/1472-6882-11-80
Abstract: In this study, guinea pigs sensitized with ovalbumin (OVA) were used as an animal model for asthma challenge, and the sensitization of animals by bronchial reactivity to methacholine (Mch) and the IgE concentration in the serum after OVA challenge were estimated. Complex traditional Chinese herbs (CTCM) were administered to the animals by nebulization, and the leukocytes were evaluated from bronchoalveolar lavage fluid (BALF).The results showed that inhalation of CTCM could abolish the increased lung resistance (13-fold increase) induced by challenge with OVA in the early asthmatic response (EAR), reducing to as low as baseline (1-fold). Moreover, our results indicated higher IgE levels (range, 78-83 ng/ml) in the serum of sensitized guinea pigs than in the unsensitized controls (0.9 ± 0.256 ng/ml). In addition, increased total leukocytes and higher levels of eosinophils and neutrophils were seen 6 hours after challenge, and the increased inflammatory cells were reduced by treatment with CTCM inhalation. The interleukin-5 (IL-5) level in BALF was also reduced by CTCM.Our findings indicate a novel method of administering traditional Chinese medicines for asthma treatment in an animal model that may be more effective than traditional methods.Bronchial asthma is a complex syndrome with many clinical symptoms. It is characterized by variable airflow obstruction, airway hyperresponsiveness and inflammation [1,2]. Provocation of the airway by inhaled allergens is followed by bronchospasm and airway smooth muscle thickening, and accumulation of eosinophils in mucosa and in bronchoalveolar lavage also occurs [1,3]. In addition, according to analyses of bronchial biopsies and lavage samples removed from allergen-exposed asthmatics, contributing to the earlier asthmatic response (EAR) and late asthmatic response (LAR) after allergen challenge [4,5], IgE-dependent activation of mast cells is present with degranulation and subsequent release of several mediators such as histami
Comparison of cough reflex sensitivity after an inhaled antigen challenge between actively and passively sensitized guinea pigs
Johsuke Hara, Masaki Fujimura, Shigeharu Myou, Yoshitaka Oribe, Shiho Furusho, Toshiyuki Kita, Nobuyuki Katayama, Miki Abo, Noriyuki Ohkura, Yoriko Herai, Akihiro Hori, Yoshihisa Ishiura, Kouichi Nobata, Haruhiko Ogawa, Masahide Yasui, Kazuo Kasahara, Shinji Nakao
Cough , 2005, DOI: 10.1186/1745-9974-1-6
Abstract: Measurement of number of coughs elicited by increasing concentrations of capsaicin (10-6 and 10-4 M) and bronchial responsiveness to ascending concentrations of methacholine, and analysis of bronchoalveolar lavage fluid (BALF) were separately performed 24 h after an antigen challenge in actively and passively sensitized guinea pigs.Percentage of eosinophils in BALF and bronchial responsiveness to methacholine were increased 24 h after the antigen challenge in both actively and passively sensitized animals compared with saline-challenged actively and passively sensitized animals, respectively. Absolute number of eosinophils in BALF from actively sensitized and antigen-challenged guinea pigs was significantly greater than that from passively sensitized and antigen-challenged animals. Cough response to capsaicin and concentration of substance P in BALF were increased 24 h after the antigen challenge in actively sensitized guinea pigs, but not in passively sensitized guinea pigs. Bronchial responsiveness, cough reflex sensitivity and substance P concentration and total cells in BALF were increased in actively sensitized and saline challenged guinea pigs compared with passively sensitized and saline challenged animals.The results suggest that active sensitization per se increases cough reflex sensitivity accompanied by increased inflammatory cells and substance P level in BALF, and antigen challenge further increases them, while simple IgE- and/or IgG-mediated allergic reaction per se or the low intensity of eosinophil infiltration in the airway itself may not affect cough reflex sensitivity in guinea pigs.Chronic cough is a common and distressing symptom. Eosinophilic airway disorders such as eosinophilic bronchitis without asthma [1] and atopic cough [2] are important causes of the chronic cough. In these disorders, cough reflex sensitivity is heightened while patients are coughing and becomes normal on successful treatment [3]. Knowledge of the detailed pathogenesis i
Preconditioning Triggered by Carbon Monoxide (CO) Provides Neuronal Protection Following Perinatal Hypoxia-Ischemia  [PDF]
Cláudia S. F. Queiroga, Simone Tomasi, Marius Wider?e, Paula M. Alves, Alessandro Vercelli, Helena L. A. Vieira
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042632
Abstract: Perinatal hypoxia-ischemia is a major cause of acute mortality in newborns and cognitive and motor impairments in children. Cerebral hypoxia-ischemia leads to excitotoxicity and necrotic and apoptotic cell death, in which mitochondria play a major role. Increased resistance against major damage can be achieved by preconditioning triggered by subtle insults. CO, a toxic molecule that is also generated endogenously, may have a role in preconditioning as low doses can protect against inflammation and apoptosis. In this study, the role of CO-induced preconditioning on neurons was addressed in vitro and in vivo. The effect of 1 h of CO treatment on neuronal death (plasmatic membrane permeabilization and chromatin condensation) and bcl-2 expression was studied in cerebellar granule cells undergoing to glutamate-induced apoptosis. CO's role was studied in vivo in the Rice-Vannucci model of neonatal hypoxia-ischemia (common carotid artery ligature +75 min at 8% oxygen). Apoptotic cells, assessed by Nissl staining were counted with a stereological approach and cleaved caspase 3-positive profiles in the hippocampus were assessed. Apoptotic hallmarks were analyzed in hippocampal extracts by Western Blot. CO inhibited excitotoxicity-induced cell death and increased Bcl-2 mRNA in primary cultures of neurons. In vivo, CO prevented hypoxia-ischemia induced apoptosis in the hippocampus, limited cytochrome c released from mitochondria and reduced activation of caspase-3. Still, Bcl-2 protein levels were higher in hippocampus of CO pre-treated rat pups. Our results show that CO preconditioning elicits a molecular cascade that limits neuronal apoptosis. This could represent an innovative therapeutic strategy for high-risk cerebral hypoxia-ischemia patients, in particular neonates.
Carbon Monoxide Targeting Mitochondria  [PDF]
Cláudia S. F. Queiroga,Ana S. Almeida,Helena L. A. Vieira
Biochemistry Research International , 2012, DOI: 10.1155/2012/749845
Abstract: Mitochondria present two key roles on cellular functioning: (i) cell metabolism, being the main cellular source of energy and (ii) modulation of cell death, by mitochondrial membrane permeabilization. Carbon monoxide (CO) is an endogenously produced gaseoustransmitter, which presents several biological functions and is involved in maintaining cell homeostasis and cytoprotection. Herein, mitochondrion is approached as the main cellular target of carbon monoxide (CO). In this paper, two main perspectives concerning CO modulation of mitochondrial functioning are evaluated. First, the role of CO on cellular metabolism, in particular oxidative phosphorylation, is discussed, namely, on: cytochrome c oxidase activity, mitochondrial respiration, oxygen consumption, mitochondrial biogenesis, and general cellular energetic status. Second, the mitochondrial pathways involved in cell death inhibition by CO are assessed, in particular the control of mitochondrial membrane permeabilization.
Myocardial Opioid Receptors in Conditioning and Cytoprotection  [PDF]
Grant Williams-Pritchard,John P. Headrick,Jason N. Peart
Pharmaceuticals , 2011, DOI: 10.3390/ph4030470
Abstract: Opioid compounds and G-protein coupled opioid receptors (ORs) have been studied widely in terms of central nervous system (CNS) actions relating to pain management and drug abuse. Opioids are also linked to induction of mammalian hibernation, a natural state of tolerance involving prolonged and orchestrated shifts in cellular metabolism, growth and stress resistance. It is not surprising then that OR agonism induces acute or delayed cytoprotective states in myocardium, rendering ORs an attractive target for protection of cardiac tissue from the potentially fatal consequences of ischemic heart disease. Cardiac ORs are implicated in triggering/mediating so-called ‘conditioning’ responses, in which powerful cytoprotection arises following transient receptor ligation prior to or immediately following ischemic insult. These responses involve one or more OR sub-types engaging pro-survival kinase cascades to ultimately modulate cell stress and mitochondrial end-effectors. However, important questions remain regarding the role of endogenous opioids, OR signalling, and the transduction and mediation of these protective responses. We briefly review opioid-mediated cardioprotection, focussing on recent developments in signal transduction, the role of receptor ‘cross-talk’, and the effects of sustained OR ligand activation.
Carbon Monoxide Targeting Mitochondria  [PDF]
Cláudia S. F. Queiroga,Ana S. Almeida,Helena L. A. Vieira
Biochemistry Research International , 2012, DOI: 10.1155/2012/749845
Abstract: Mitochondria present two key roles on cellular functioning: (i) cell metabolism, being the main cellular source of energy and (ii) modulation of cell death, by mitochondrial membrane permeabilization. Carbon monoxide (CO) is an endogenously produced gaseoustransmitter, which presents several biological functions and is involved in maintaining cell homeostasis and cytoprotection. Herein, mitochondrion is approached as the main cellular target of carbon monoxide (CO). In this paper, two main perspectives concerning CO modulation of mitochondrial functioning are evaluated. First, the role of CO on cellular metabolism, in particular oxidative phosphorylation, is discussed, namely, on: cytochrome c oxidase activity, mitochondrial respiration, oxygen consumption, mitochondrial biogenesis, and general cellular energetic status. Second, the mitochondrial pathways involved in cell death inhibition by CO are assessed, in particular the control of mitochondrial membrane permeabilization. 1. Introduction Carbon monoxide (CO) is a colorless and odorless small molecule, widely known as a lethal gas and as a toxic air pollutant. CO toxicity was disclosed in 1912 by Douglas [1]; its high affinity for haemglobin, forming carboxyhaemglobin, compromises oxygen delivery in tissues and subsequently causes lethality. Several decades later, CO was found as an endogenous generated gas in humans [2, 3]. However, only in the late sixties, haem oxygenase (HO) was characterized as the enzyme responsible for haem cleavage, with the release of CO, free iron (Fe2+) and biliverdin [4, 5]. There are two genetically distinct isozymes for HO: an inducible form haem-oxygenase-1 (HO-1) and a constitutively expressed form haem oxygenase-2 (HO-2). HO-1 occurs mainly in spleen, liver or bone marrow, and tissues that degrade senescent red blood cells; under conditions of haemolysis its activity dramatically increases. Higher levels of HO-2 occur mainly in testes and central nervous system [6]. Increase expression of HO-1 is associated with biological responses to several sources of stress, namely, oxidative stress, hypoxia, hyperoxia, misfolded protein response, hyperthermia, tumour promoter, ultraviolet radiation, and so forth. Concomitant with the increasing importance of HO activity in biological systems, CO is largely recognized as a homeostatic and cytoprotective molecule [7, 8]. Stimulation of endogenously generated CO and/or low doses of applied CO have shown to exert remarkable beneficial biological effects in many tissues: anti-inflammatory, antiapoptotic, antiproliferative and
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