August 29, 2013
American Autoimmune Related Diseases Association (AARDA)
First large scale study links autism and autoimmunity
https://www.sciencedaily.com/releases/2 ... 092648.htm
A new, large-scale study of more than 2,700 mothers of children with autism shows that about one in 10 mothers have antibodies in their bloodstream that react with proteins in the brain of their babies.
The research, published in Molecular Psychology (August 20, 2013) indicates that while the blood-brain barrier in the adult women prevents them from being harmed by the antibodies.....
Association of Schools and Programs of Public Health, hosted by National Center for Environmental Assessment, Office of Research and Development, United States
Ambient ozone and fine particulate matter exposures and autism spectrum disorder in metropolitan Cincinnati, Ohio.
We detected elevated aORs for PM2.5 during the 2nd trimester, 1st year of life, and a cumulative period from pregnancy through the 2nd year (aOR ranges across categories: 1.41-1.44, 1.54-1.84, and 1.41-1.52 respectively), and for ozone in the 2nd year of life (aOR range across categories: 1.29-1.42). Per each change in IQR, we observed elevated aORs for ozone in the 3rd trimester, 1st and 2nd years of life, and the cumulative period (aOR range: 1.19-1.27) and for PM2.5 in the 2nd trimester, 1st year of life, and the cumulative period (aOR range: 1.11-1.17).
Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Querétaro, Mexico
Effect of Ozone Exposure on Dendritic Spines of CA1 Pyramidal Neurons of the Dorsal Hippocampus and on Object-place Recognition Memory in Rats.
The growth of many cities has generated an increase in the emission of environmental pollutants. Exposure to these pollutants has been associated with increased mortality worldwide. These pollutants, such as ozone, produce reactive oxygen species (ROS), which cause oxidative stress throughout the body. It has been observed that there is a relationship between chronic oxidative stress and the development of degenerative diseases typical of old age such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. The purpose of this research was to evaluate whether chronic exposure to ozone produces a deleterious effect on density and morphology of dendritic spines in CA1 of dorsal hippocampus and on learning and memory of object-place recognition. Rats were exposed to ozone or to ozone-free air for a period of 15, 30, 60, or 90 days. The principal results indicate that chronic oxidative stress induced by ozone produces a decrease in the density of dendritic spines, a decrease in thin and mushroom spine ratios, and an increase in stubby spine ratio, as well as a deficit in learning and memory of the object-place recognition task. These results indicate that chronic ozone exposure produces a loss in the inputs of CA1 neurons of the dorsal hippocampus, which may be the source of the cognitive deficits observed in the object-place recognition task, as indicated by the decrease in density of dendritic spines; these alterations are similar to those reported in some neurodegenerative diseases such as Alzheimer's disease.
Laboratorio de Neurofisiología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Jalisco, Mexico
Curcumin Exerted Neuroprotection against Ozone-Induced Oxidative Damage and Decreased NF-κB Activation in Rat Hippocampus and Serum Levels of Inflammatory Cytokines.
Ozone is a harmful tropospheric pollutant, causing the formation of reactive oxygen and nitrogen species that lead to oxidative damage in living beings. NF-κB can be activated in response to oxidative damage, inducing an inflammatory response. Nowadays, there are no reliable results that consolidate the use of antioxidants to protect from damage caused by ozone, particularly in highly polluted cities. Curcumin has a strong antioxidant activity and is a potent inhibitor of NF-κB activation with no side effects. The aim of this study is to evaluate the effect of curcumin in preventive and therapeutic approaches against oxidative damage, NF-κB activation, and the rise in serum levels of IL-1β and TNF-α induced by acute and chronic exposure to ozone in rat hippocampus. One hundred male Wistar rats were distributed into five groups; the intact control, curcumin-fed control, the ozone-exposed group, and the preventive and therapeutic groups. These last two groups were exposed to ozone and received food supplemented with curcumin. Lipid peroxidation was determined by spectrophotometry, and protein oxidation was evaluated by immunodetection of carbonylated proteins and densitometry analysis. Activation of NF-κB was assessed by electrophoretic mobility shift assay (EMSA), and inflammatory cytokines (IL-1β and TNF-α) were determined by ELISA. Curcumin decreased NF-κB activation and serum levels of inflammatory cytokines as well as protein and lipid oxidation, in both therapeutic and preventive approaches. Curcumin has proven to be a phytodrug against the damage caused by the environmental exposure to ozone.
Department of Occupational and Environmental Health Sciences, Peking University School of Public Health, and Peking University Institute of Environmental Medicine, Key Laboratory of Molecular Cardiovascular Sciences of the Ministry of Education, Health Science Center, Peking University Medicine, China
Ambient air pollution is associated with cardiac repolarization abnormalities in healthy adults
Ambient air pollution has been associated with acute cardiovascular events; however, the underlying mechanisms remain incompletely understood. We aimed to examine the impacts of ambient air pollutants on cardiac ventricular repolarization in a highly polluted urban region.
Seventy-three healthy non-smoking young adults (66% female, mean age of 23.3 ± 5.4 years) were followed with four repeated 24-h electrocardiogram recordings in 2014-2016 in Beijing, China. Continuous concentrations of ambient particulates in size fractions of 5-560 nm diameter, black carbon (BC), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3) were measured at a fixed-location air pollution monitoring station. Generalized linear mixed models, with adjustment for individual risk factors, time-varying factors and meteorological parameters, were used to evaluate the effects of air pollution on 5-min segments of heart rate-corrected QT interval (QTc), an index of cardiac ventricular repolarization.
During the study period, the mean levels of number concentrations of particulates in size range of 5-560 nm (PNC5-560) were 20,711 particles/cm3. Significant increases in QTc of 0.56% (95% CI: 0.27, 0.84) to 1.76% (95% CI: 0.73, 2.79) were associated with interquartile range increases in PNC50-560 at prior 1-5 moving average days. Significant increases in QTc were also associated with increases in exposures to traffic-related air pollutants (BC, NO2 and CO), a combustion pollutant SO2, and the secondary pollutant O3. The associations were stronger in participants who were male, overweight, with abdominal obesity, and with higher levels of high-sensitivity C-reactive protein.
Our findings suggest that exposures to higher levels of ambient particulates in small size fractions and traffic pollutants were associated with cardiac repolarization abnormalities in healthy adults, and the cardio-metabolic risks may modify the adverse cardiac effects attributable to air pollution.
N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia
Rate constants for interaction reactions of ozone with palmitic, oleic and others fatty acids. Role of ozonolysis in metabolism of fatty acids
Impacts of air pollution on human and ecosystem health, and implications for the National Emission Ceilings Directive: Insights from Italy.
..Across the 28 EU member states there were nearly half a million premature deaths in 2015 as a result of exposure to PM2.5, O3 and NO2. To set the target for air quality levels and avoid negative impacts for human and ecosystems health, the National Emission Ceilings Directive..
Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Association between air pollution and sleep disordered breathing in children.
BACKGROUND AND OBJECTIVE:
Similar to other respiratory diseases, sleep disordered breathing (SDB) may be exacerbated by air contaminants. Air pollution may have an impact on incidence and severity of SDB in children. The aims of this study were to examine potential associations between the exposure to different air pollutants and SDB symptoms in children.
Department of Urology, Peking University Third Hospital, Beijing, China
Ambient ozone pollution is associated with decreased semen quality: longitudinal analysis of 8945 semen samples from 2015 to 2018 and during pollution-control period in Beijing
Previous studies suggest that air pollution has a negative effect on semen quality. However, most studies are cross-sectional and the results are controversial. This study investigated the associations between air pollutants (PM2.5, PM10, SO2, NO2, CO, and O3) and semen quality among sperm donation candidates, especially when the air pollution was artificially controlled in Beijing, China. We analyzed 8945 semen samples in the human sperm bank of Peking University Third Hospital (Beijing, China) from October 2015 to May 2018. Air pollution data during the entire period (0-90 days prior) and key stages (0-9, 10-14, and 70-90 days prior) of sperm development were collected from the China National Environmental Monitoring Centre. The association between air pollutants and semen parameters (sperm concentration and progressive motility) was analyzed by a mixed model adjusted for age, abstinence duration, month, and average ambient temperature. Only O3 during key stages of 0-9 days and 10-14 days and the entire period was negatively associated with sperm concentration between 2015 and 2018 (P < 0.01). During the period of air pollution control from November 2017 to January 2018, except for the increase in O3 concentration, other five pollutants' concentrations decreased compared to those in previous years. In this period, the sperm concentration decreased (P < 0.001). During the pollution-control period, O3 exposure 10-14 days prior was negatively associated with sperm concentration (95% CI: -0.399--0.111; P < 0.001). No significant association was found between the other five pollutants and semen quality during that period. Our study suggested that only O3exposure was harmful to semen quality. Therefore, O3 should not be neglected during pollution control operation.
IUF - Leibniz-Institut für umweltmedizinische Forschung, Düsseldorf, Deutschland
Skin damage by tropospheric ozone
The influence of maternal and perinatal high-fat diet on ozone-induced pulmonary responses in offspring.
Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México
Ozone pollution, oxidative stress, synaptic plasticity, and neurodegeneration
Overpopulation and industrial growth result in an increase in air pollution, mainly due to suspended particulate matter and the formation of ozone. Repeated exposure to low doses of ozone, such as on a day with high air pollution levels, results in a state of chronic oxidative stress, causing the loss of dendritic spines, alterations in cerebral plasticity and in learning and memory mechanisms, and neuronal death and a loss of brain repair capacity. This has a direct impact on human health, increasing the incidence of chronic and degenerative diseases.
We performed a search of the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2000 and 2018 and addressing the main consequences of ozone exposure on synaptic plasticity, information processing in cognitive processes, and the alterations that may lead to the development of neurodegenerative diseases.
This review describes one of the pathophysiological mechanisms of the effect of repeated exposure to low doses of ozone, which causes loss of synaptic plasticity by producing a state of chronic oxidative stress. This brain function is key to both information processing and the generation of structural changes in neuronal populations. We also address the effect of chronic ozone exposure on brain tissue and the close relationship between ozone pollution and the appearance and progression of neurodegenerative diseases.
2019 Dec 13
Department of Molecular Biology and Genetics, Apoptosis and Cancer Immunology Laboratory (AKIL), Boğaziçi University, İstanbul Turkey
The NLRP3 inflammasome: a new player in neurological diseases
Inflammasomes are supramolecular protein complexes implicated in the detection of pathogens or danger-associated molecules and are responsible for mounting the first line of innate immune response to counteract these signals and restore tissue homeostasis. Among different inflammasomes identified so far, NLRP3 is of main interest since mutations in Nlrp3 gene are associated with autoinflammatory diseases such as Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, and familial cold urticaria/autoinflammatory syndrome. On the other hand, whereas other inflammasomes are mainly detectors of specific molecular motifs, NLRP3 is acting as a general sensor of cellular perturbations including potassium efflux, lysosomal damage, and ROS production. Besides this central role of NLRP3 in inflammation, recent publications show that the NLRP3 inflammasome is also involved in the physiopathology of several neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review gives an overview of the established functions of the NLRP3 inflammasome in mediating inflammation in macrophages and describes its recently discovered roles in neurological disorders in promoting neuroinflammation, as well as modulating key proteins mediating the disorders. Finally, we discuss the targeting of NLRP3 in neurological diseases and present some examples of NLRP3 inhibitors that could be used in neurological disorder treatments.
Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University , Shanghai , China
Mitochondrial ROS and NLRP3 inflammasome in acute ozone-induced murine model of airway inflammation and bronchial hyperresponsiveness.
Oxidative stress is a key mechanism underlying ozone-induced lung injury. Mitochondria can release mitochondrial reactive oxidative species (mtROS), which may lead to the activation of NLRP3 inflammasome. The goal of this study was to examine the roles of mtROS and NLRP3 inflammasome in acute ozone-induced airway inflammation and bronchial hyperresponsiveness (BHR). C57/BL6 mice (n = 8/group) were intraperitoneally treated with vehicle (phosphate buffered saline, PBS) or mitoTEMPO (mtROS inhibitor, 20 mg/kg), or orally treated with VX-765 (caspse-1 inhibitor, 100 mg/kg) 1 h before the ozone exposure (2.5 ppm, 3 h). Compared to the PBS-treated ozone-exposed mice, mitoTEMPO reduced the level of total malondialdehyde in bronchoalveolar lavage (BAL) fluid and increased the expression of mitochondrial complexes II and IV in the lung 24 h after single ozone exposure. VX-765 inhibited ozone-induced BHR, BAL total cells including neutrophils and eosinophils, and BAL inflammatory cytokines including IL-1α, IL-1β, KC, and IL-6. Both mitoTEMPO and VX-765 reduced ozone-induced mtROS and inhibited capase-1 activity in lung tissue whilst VX-765 further inhibited DRP1 and MFF expression, increased MFN2 expression, and down-regulated caspase-1 expression in the lung tissue. These results indicate that acute ozone exposure induces mitochondrial dysfunction and NLRP3 inflammasome activation, while the latter has a critical role in the pathogenesis of ozone-induced airway inflammation and BHR.
2020 Jan 3
Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana, Rome, Italy
'Prototypical' proinflammatory cytokine (IL-1) in multiple sclerosis: role in pathogenesis and therapeutic targeting.
Introduction: It has been recognized for about 20 years that interleukin (IL)-1 signaling is implicated in Multiple Sclerosis (MS), a disabling, chronic, inflammatory and neurodegenerative disease of the central nervous system (CNS). Only recently, multifaceted roles of IL-1 emerged in MS pathophysiology as a result of both clinical and preclinical studies. Notably, drugs that directly target the IL-1 system have not been tested so far in MS.Areas covered: Recent studies in animal models, together with the development of ex vivo chimeric MS models, have disclosed a critical role for IL-1 not only at the peripheral level but also within the CNS. In the present review, we highlight the IL-1-dependent neuropathological aspects of MS, by providing an overview of the cells of the immune and CNS systems that respond to IL-1 signaling, and by emphasizing the subsequent effects on the CNS, from demyelinating processes, to synaptopathy, and excitotoxicity.Expert opinion: Drugs that act on the IL-1 system show a therapeutic potential in several autoinflammatory diseases and preclinical studies have highlighted the effects of these compounds in MS. We will discuss why anti-IL-1 therapies in MS have been neglected to date.
Chloé Michaudel, Aurélie Couturier-Maillard, [...], and Bernhard Ryffel
Inflammasome, IL-1 and inflammation in ozone-induced lung injury
Exposure to ambient ozone causes airway hyperreactivity and lung inflammation, which represent an important health concern in humans. Recent clinical and experimental studies contributed to the understanding of the mechanisms of epithelial
The IL-1 axis is associated with airway inflammation after O3 exposure in allergic asthmatics
2018 Dec 21
Department of Neurology, University of Regensburg, Regensburg, Germany
The Impact of Coffee and Caffeine on Multiple Sclerosis Compared to Other Neurodegenerative Diseases
.. Results: Higher intake of coffee and caffeine was associated with a lower risk of developing PD. In some of the MS studies there, is evidence for a similar effect and experimental studies confirmed the positive impact. Interestingly in MS coffee and caffeine may have a stronger impact on disease course compared to effects on disease susceptibility. In ALS no such beneficial effect could be observed in the clinical and experimental studies
2020 Jan 10
Department of Mechanical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan
Evaluation of Ozone Removal by Spent Coffee Grounds
Activated carbon is the most known material used to adsorb ozone. Activating carbonaceous materials by ozonation is commonly used to produce activated carbon, however, requiring sophisticated skills and professional equipment. This paper presents a reversed idea: to adsorb ozone using an unactivated carbonaceous material, coffee. Three powder adsorbents are presented: fresh coffee (unactivated), spent coffee grounds (unactivated), and activated carbon (commercially available). The test is conducted by measuring and comparing the ozone concentration in an ozone-supplied chamber with or without the ozone adsorbent. The results show that, at the specific conditions, the peak ozone concentration is lowered by 38% to 56% when the chamber has the activated carbon. At the same conditions, the peak ozone concentration is lowered by 25% to 43% when the chamber has the coffee powders (either fresh or spent). The elemental analysis demonstrates that the oxygen content after the ozone adsorption increases by 20%, 14.4%, and 34.5% for the fresh coffee, the spent coffee grounds, and the activated carbon, respectively. The characteristic analysis (the Fourier-transform infrared spectroscopy, the thermogravimetric, and the Brunauer-Emmett-Teller) suggests that the unactivated coffee is not porous, however, contains various organic compounds that could react with and consume ozone.
Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Assessing Adverse Health Effects of Long-Term Exposure to Low Levels of Ambient Air Pollution: Phase 1.
This report provides a summary of major findings and key conclusions supported by a Health Effects Institute grant aimed at "Assessing Adverse Health Effects of Long-Term Exposure to Low Levels of Ambient Pollution." Our study was designed to advance four critical areas of inquiry and methods development...
Our HEI-funded work has supported an extensive portfolio of analysis and the development of statistical methods that can be used to robustly understand the health effects of long- and short-term exposure to low levels of ambient air pollution. This report provides a high-level overview of statistical methods, data analysis, and key findings, as grouped into the following four areas: (1) Exposure assessment and data access; (2) Epidemiological studies of ambient exposures to air pollution at low levels; (3) Methodological contributions in causal inference; and (4) Open science research data platform.
Our body of work, advanced by HEI, lends extensive evidence that short- and long-term exposure to PM2.5 and O3 is harmful to human health, increasing the risks of hospitalization and death, even at levels that are well below the National Ambient Air Quality Standards (NAAQS).
https://www.facebook.com/ale.biole/medi ... 494&type=3
The Bee Therapy House -
2020 Bee barrier
Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung City, Taiwan
Indoor Ozone and Particulate Matter Modify the Association Between Airborne Endotoxin and Schoolchildren's Lung Function
Background: To date, the effect of household airborne pollutants on the association between airborne endotoxin and lung function of schoolchildren is unknown.
Objectives: The objective of this study is to evaluate whether indoor air pollutants such as carbon monoxide (CO), carbon dioxide (CO2), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), particulate matter with aerodynamic diameter <10 and 2.5 μm (PM10, PM2.5) can modify the association between airborne endotoxin and school children's lung function in a heavy industrial city in Taiwan.
Methods: We recruited 120 elementary school-age children in Kaohsiung City, Taiwan. Aerosol samples were collected on a filter membrane for 24 h period and then analyzed for endotoxin. Air pollutants were measured for 24 h in living rooms while school children's lung function was measured. The modification of air pollutants on the relationship between airborne endotoxin and children's lung function was estimated after adjusting the gender, age, height, weight, and case-control status.
Results: We found that both O3 and PM10 concentrations significantly modified the relationships between airborne endotoxin and school children's lung function. Among children living in homes with O3 ≥ 0.01 ppm or PM10 ≥ 62 μg/m3, airborne endotoxin was negatively associated with lung functions, whereas among those living in homes with O3 < 0.01 ppm or PM10 < 62 μg/m3, airborne endotoxin was positively associated with lung functions.
Conclusions: The indoor air pollutant concentration of O3 and PM10 modifies the association between airborne endotoxin and school children's lung function.
Institute of Biosciences, Department of Microbiology and Immunology, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
Should Mast Cells Be Considered Therapeutic Targets in Multiple Sclerosis?
Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.
Mechanisms of Response to Ozone Exposure: The Role of Mast Cells in Mice
https://cfpub.epa.gov/ncer_abstracts/in ... tract/2357
Ozone is a highly reactive gas and a major component of photochemical oxidant air pollution. Short-term exposure to ozone can cause a transient migration of inflammatory cells to the airways. Less is known about the effects of prolonged or repeated exposures. There is concern, however, that such exposures may cause chronic inflammation that could permanently damage the small airways because inflammatory cells release substances that injure the epithelial cells lining airway surfaces...
MSPetr75 wrote: ↑Thu Sep 12, 2019 10:49 am MS
Department of Neurology , Isfahan University of Medical Sciences , Isfahan , The Islamic Republic of Iran
Elevated CSF concentration of CCL3 and CCL4 in relapsing remitting multiple sclerosis patients
CCL3 and CCL4 are considered as inflammatory cytokines and involved in progression of various neurologic disorders as multiple sclerosis (MS). The aim of this study was to evaluate the association between cerebrospinal fluid (CSF) levels of above mentioned inflammatory cytokines and relapsing remitting multiple sclerosis (RRMS. In this case-control study, 40 unrelated patients (without family relationship) with RRMS and 40 age and sex matched subjects as control group were enrolled. CSF samples obtained from all patients and control group and levels of CCL3 and CCL4 were determined in CSF. The mean CSF level of CCL3 was significantly higher in RRMS patients than healthy controls (29.71±18.56 vs. 10.62±6.85, p<0.01). The CSF levels of CCL4 was also higher in RRMS patients compared with healthy controls (33.62±21.50 vs. 13.74±4.90, p<0.01). We found a positive correlation between CSF levels of CCL3 and disease duration (r=+0.32 and p=0.04) and expanded disability status scale (EDSS) (r=+45, p=0.03). We also found a positive correlation between CSF level of CCL4 and disease duration (r=+0.76 and p<0.01) and EDSS (r=+0.73, p<0.01). Present study showed contribution of CCL3 and CCL4 in MS pathogenesis and suggested them as markers of severity of disease. Investigation of chemokines responsible for attract of pathogenic T lymphocyte and macrophage in to the central nerves system(CNS) is crucial for therapeutic targets in MS
Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey
Editor's Highlight: Role of Spleen-Derived Macrophages in Ozone-Induced Lung Inflammation and Injury.
Macrophages and inflammatory mediators have been implicated in ozone toxicity. In these studies, we used splenectomized (SPX) mice to assess the contribution of splenic monocytes to pulmonary inflammation and injury induced by ozone. Cells and tissue were collected 24-72 h after exposure of mice to air or ozone (0.8 ppm, 3 h). Following ozone exposure, increased numbers of pro-inflammatory CD11b + Ly6CHi and anti-inflammatory CD11b + Ly6CLo monocytes were observed in spleens of control (CTL) mice. CD11b + Ly6CHi and MMP-9+ pro-inflammatory macrophages were also observed in lungs of CTL mice after ozone, along with CD11b + Ly6CLo and mannose receptor (MR)+ anti-inflammatory macrophages. This was accompanied by increased lung expression of proteins involved in monocyte/macrophage trafficking including CCL3, CCL4, CCR1, and AT1R. Splenectomy resulted in decreases in pro-inflammatory macrophages in the lung and down regulation of CCR2, CCL2, and CCL4, but increases in CD11b + Ly6CLo anti-inflammatory macrophages. CD11b+Ly6G+Ly6C+ granulocytic (G)- and monocytic (M)-myeloid derived suppressor cells (MDSC)s were also detected in the lungs and spleens of CTL mice; these increased after ozone exposure. Splenectomy was associated with a decrease in G-MDSCs in the lung, with no effect on M-MDSCs. Changes in lung macrophage subpopulations and MDSCs in SPX mice were correlated with reduced ozone toxicity, as measured by decreases in bronchoalveolar lavage protein content and reduced 4-hydroxynonenal expression in the lung. These data suggest that the spleen is a source of pro-inflammatory/cytotoxic macrophages that contribute to ozone-induced lung injury, inflammation, and oxidative stress.
2020 May 5
Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
Investigating the Causal Effect of Brain Expression of CCL2, NFKB1, MAPK14, TNFRSF1A, CXCL10 Genes on Multiple Sclerosis: A Two-Sample Mendelian Randomization Approach
Multiple Sclerosis (MS) exhibits considerable heterogeneity in phenotypic expression, course, prognosis and response to therapy. This suggests this disease involves multiple, as yet poorly understood, causal mechanisms. In this work we assessed the possible causal link between gene expression level of five selected genes related to the pro-inflammatory NF-κB signaling pathway (i.e., CCL2, NFKB1, MAPK14, TNFRSF1A, CXCL10) in ten different brain tissues (i.e., cerebellum, frontal cortex, hippocampus, medulla, occipital cortex, putamen, substantia nigra, thalamus, temporal cortex and intralobular white matter) and MS. We adopted a two-stage Mendelian Randomization (MR) approach for the estimation of the causal effects of interest, based on summary-level data from 20 multiplex Sardinian families and data provided by the United Kingdom Brain Expression Consortium (UKBEC). Through Radial-MR and Cochrane's Q statistics we identified and removed genetic variants which are most likely to be invalid instruments. To estimate the total causal effect, univariable MR was carried out separately for each gene and brain region. We used Inverse-Variance Weighted estimator (IVW) as main analysis and MR-Egger Regression estimator (MR-ER) and Weighted Median Estimator (WME) as sensitivity analysis. As these genes belong to the same pathway and thus they can be closely related, we also estimated their direct causal effects by applying IVW and MR-ER within a multivariable MR (MVMR) approach using set of genetic instruments specific and common (composite) to each multiple exposures represented by the expression of the candidate genes. Univariate MR analysis showed a significant positive total causal effect for CCL2 and NFKB1 respectively in medulla and cerebellum. MVMR showed a direct positive causal effect for NFKB1 and TNFRSF1A, and a direct negative causal effect for CCL2 in cerebellum; while in medulla we observed a direct positive causal effect for CCL2. Since in general we observed a different magnitude for the gene specific causal effect we hypothesize that in cerebellum and medulla the effect of each gene expression is direct but also mediated by the others. These results confirm the importance of the involvement of NF-κB signaling pathway in brain tissue for the development of the disease and improve our understanding in the pathogenesis of MS.