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The pulmonary system represents a unique lipidomic environment as it contains cellular membrane bound lipid species and a specialized reservoir of lipids in the airway epithelial lining fluid. As a major initial point of defense, airway lipids react to inhaled contaminants such as volatile organic compounds, oxides of nitrogen, or ozone (O3), creating lipokine signaling that is crucial for both the initiation and resolution of inflammation within the lung. Dietary modulation of eicosanoids has gained increased attention in recent years for improvements to cardiovascular health. The current study sought to examine how dietary supplementation with eicosanoid precursors (i.e., oils rich in saturated or polyunsaturated fatty acids) might alter the lung lipid composition and subsequently modify the inflammatory response to ozone inhalation. Our study demonstrated that mice fed a diet high in saturated fatty acids resulted in diet-specific changes to lung lipid profiles and increased cellular recruitment to the lung following ozone inhalation. Bioinformatic analysis revealed an ozone-dependent upregulation of several lipid species, including phosphoserine 37:5. Pathway analysis of lipid species revealed the process of lateral diffusion of lipids within membranes to be significantly altered due to ozone exposure. These results show promising data for influencing pulmonary lipidomic profiles via diet, which may provide a pragmatic therapeutic approach to protect against lung inflammation and damage following pulmonary insult.
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The contribution of air pollution-induced cardiopulmonary damage on the development of hypertensive disorders of pregnancy and other adverse outcomes of pregnancy has gained increased attention as epidemiological data continue to highlight spatiotemporal pregnancy trends related to air pollution exposure. However clinical mechanistic data surrounding gestational complications remain sparse, necessitating the need for the use of animal models to study these types of complications of pregnancy. The current study seeks to examine the real-time effects of mid-gestational ozone exposure on maternal blood pressure and body temperature through the use of radiotelemetry in a rat model. The exposure resulted in acute depression of heart rate and core body temperature as compared to control animals. Ozone-exposed animals also presented with a slight but significant increase in arterial blood pressure which was perpetuated until term. The data presented here illustrates the feasibility of murine models to assess cardiovascular complications caused by inhaled toxicants during the window of pregnancy.
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Modelos Animales de Enfermedad , Frecuencia Cardíaca , Hipertensión Inducida en el Embarazo , Ozono , Animales , Embarazo , Femenino , Ozono/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión Inducida en el Embarazo/inducido químicamente , Hipertensión Inducida en el Embarazo/fisiopatología , Factores de Tiempo , Presión Arterial/efectos de los fármacos , Ratas Sprague-Dawley , Contaminantes Atmosféricos/toxicidad , Edad Gestacional , Exposición por Inhalación/efectos adversos , Telemetría , Ratas , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Exposición Materna/efectos adversosRESUMEN
BACKGROUND: Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. OBJECTIVES: This study aims to investigate the impacts of polymer microspheres on tissue metabolism in mice by assessing the microspheres ability to translocate across the gut barrier and enter into systemic circulation. Specifically, we wanted to examine microsphere accumulation in different organ systems, identify concentration-dependent metabolic changes, and evaluate the effects of mixed microsphere exposures on health outcomes. METHODS: To investigate the impact of ingested microspheres on target metabolic pathways, mice were exposed to either polystyrene (5µm) microspheres or a mixture of polymer microspheres consisting of polystyrene (5µm), polyethylene (1-4µm), and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid) (5µm). Exposures were performed twice a week for 4 weeks at a concentration of either 0, 2, or 4mg/week via oral gastric gavage. Tissues were collected to examine microsphere ingress and changes in metabolites. RESULTS: In mice that ingested microspheres, we detected polystyrene microspheres in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolic differences that occurred in the colon, liver, and brain, which showed differential responses that were dependent on concentration and type of microsphere exposure. DISCUSSION: This study uses a mouse model to provide critical insight into the potential health implications of the pervasive issue of plastic pollution. These findings demonstrate that orally consumed polystyrene or mixed polymer microspheres can accumulate in tissues such as the brain, liver, and kidney. Furthermore, this study highlights concentration-dependent and polymer type-specific metabolic changes in the colon, liver, and brain after plastic microsphere exposure. These results underline the mobility within and between biological tissues of MPs after exposure and emphasize the importance of understanding their metabolic impact. https://doi.org/10.1289/EHP13435.
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Poliestirenos , Contaminantes Químicos del Agua , Humanos , Animales , Ratones , Microesferas , Plásticos , Distribución Tisular , Microplásticos , Contaminantes Químicos del Agua/análisisRESUMEN
The contribution of air pollution induced cardio-pulmonary damage on the development of hypertensive disorders of pregnancy and other adverse outcomes of pregnancy has gained increased attention as epidemiological data continues to highlight spatiotemporal pregnancy trends related to air pollution exposure. However clinical mechanistic data surrounding gestational complications remains sparse, necessitating the need for the use of animal models to study these types of complications of pregnancy. The current study seeks to examine the real-time effects of mid-gestational ozone exposure on maternal blood pressure and body temperature through the use of radiotelemetry in a rat model. The exposure resulted in acute depression of heart rate and core body temperature as compared to control animals. Ozone exposed animals also presented with a slight but significant increase in arterial blood pressure which was perpetuated until term. The data presented here illustrates the feasibility of murine models to assess cardiovascular complications caused by inhaled toxicants during the window of pregnancy.
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Ozone (O3) is a criteria air pollutant with the most frequent incidence of exceeding air quality standards. Inhalation of O3 is known to cause lung inflammation and consequent systemic health effects, including endothelial dysfunction. Epidemiologic data have shown that gestational exposure to air pollutants correlates with complications of pregnancy, including low birth weight, intrauterine growth deficiency, preeclampsia, and premature birth. Mechanisms underlying how air pollution may facilitate or exacerbate gestational complications remain poorly defined. The current study sought to uncover how gestational O3 exposure impacted maternal cardiovascular function, as well as the development of the placenta. Pregnant mice were exposed to 1PPM O3 or a sham filtered air (FA) exposure for 4 h on gestational day (GD) 10.5, and evaluated for cardiac function via echocardiography on GD18.5. Echocardiography revealed a significant reduction in maternal stroke volume and ejection fraction in maternally exposed dams. To examine the impact of maternal O3 exposure on the maternal-fetal interface, placentae were analyzed by single-cell RNA sequencing analysis. Mid-gestational O3 exposure led to significant differential expression of 4021 transcripts compared with controls, and pericytes displayed the greatest transcriptional modulation. Pathway analysis identified extracellular matrix organization to be significantly altered after the exposure, with the greatest modifications in trophoblasts, pericytes, and endothelial cells. This study provides insights into potential molecular processes during pregnancy that may be altered due to the inhalation of environmental toxicants.
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Contaminantes Atmosféricos , Contaminación del Aire , Cardiopatías , Ozono , Humanos , Femenino , Embarazo , Animales , Ratones , Células Endoteliales , Pericitos , Material Particulado , Placenta , Contaminantes Atmosféricos/toxicidad , Exposición Materna/efectos adversosRESUMEN
Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0.5 mg/m3. Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-day post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of CD31Hi and CD31Med expressors, with wood smoke inhalation causing an increased proportion of CD31Hi. These populations of CD31Hi and CD31Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b+/CD45low) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules, such as glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD+ metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD+ abundance on day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated with wildfire smoke exposure.
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NAD , Enfermedades Neuroinflamatorias , Femenino , Animales , Ratones , Ratones Endogámicos C57BL , Biomasa , Hipocampo , Ácido Glutámico , Metabolómica , Humo/efectos adversosRESUMEN
Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. To investigate the impact of ingested MPs on target metabolomic pathways, mice were subjected to either polystyrene microspheres or a mixed plastics (5 µm) exposure consisting of polystyrene, polyethylene and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid). Exposures were performed twice a week for four weeks at a dose of either 0, 2, or 4 mg/week via oral gastric gavage. Our findings demonstrate that, in mice, ingested MPs can pass through the gut barrier, be translocated through the systemic circulation, and accumulate in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolomic changes that occur in the colon, liver and brain which show differential responses that are dependent on dose and type of MPs exposure. Lastly, our study provides proof of concept for identifying metabolomic alterations associated with MPs exposure and adds insight into the potential health risks that mixed MPs contamination may pose to humans.
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Epidemiological studies have established that exposure to tungsten increases the risk of developing cardiovascular diseases. However, no studies have investigated how tungsten affects cardiac function or the development of cardiovascular disease. Inhalation of tungsten particulates is relevant in occupational settings, and inhalation of particulate matter has a known causative role in driving cardiovascular disease. This study examined if acute inhalation to tungsten particulates affects cardiac function and leads to heart tissue alterations. Female BALB/c mice were exposed to Filtered Air or 1.5 ± 0.23 mg/m3 tungsten particles, using a whole-body inhalation chamber, 4 times over the course of two weeks. Inhalation exposure resulted in mild pulmonary inflammation characterized by an increased percentage and number of macrophages and metabolomic changes in the lungs. Cardiac output was significantly decreased in the tungsten-exposed group. Additionally, A', an indicator of the amount of work required by the atria to fill the heart was elevated. Cardiac gene expression analysis revealed, tungsten exposure increased expression of pro-inflammatory cytokines, markers of remodeling and fibrosis, and oxidative stress genes. These data strongly suggest exposure to tungsten results in cardiac injury characterized by early signs of diastolic dysfunction. Functional findings are in parallel, demonstrating cardiac oxidative stress, inflammation, and early fibrotic changes. Tungsten accumulation data would suggest these cardiac changes are driven by systemic consequences of pulmonary damage.
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Enfermedades Cardiovasculares , Neumonía , Ratones , Animales , Femenino , Tungsteno/toxicidad , Enfermedades Cardiovasculares/metabolismo , Pulmón/metabolismo , Material Particulado/toxicidad , Neumonía/metabolismo , Exposición por Inhalación/efectos adversosRESUMEN
Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the neuroinflammatory and metabolomic temporal dynamics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6J mice were exposed to wood smoke every other day for two weeks at an average exposure concentration of 0.5mg/m 3 . Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-days post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of PECAM (CD31), high and medium expressors, with wood smoke inhalation causing an increased proportion of PECAM Hi . These populations of PECAM Hi and PECAM Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b + /CD45 low ) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules like glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD + metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD + abundance at day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated wtith wildfire smoke exposure.
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Electronic cigarette (Ecig) use has become more common, gaining increasing acceptance as a safer alternative to tobacco smoking. However, the 2019 outbreak of Ecig and Vaping-Associated Lung Injury (EVALI) alerted the community to the potential for incorporation of deleterious ingredients such as vitamin E acetate into products without adequate safety testing. Understanding Ecig induced molecular changes in the lung and systemically can provide a path to safety assessment and protect consumers from unsafe formulations. While vitamin E acetate has been largely removed from commercial and illicit products, many Ecig products contain additives that remain largely uncharacterized. In this study, we determined the lung-specific effects as well as systemic immune effects in response to exposure to a common Ecig base, propylene glycol and vegetable glycerin (PGVG), with and without a 1% addition of phytol, a diterpene alcohol that has been found in commercial products. We exposed animals to PGVG with and without phytol and assessed metabolite, lipid, and transcriptional markers in the lung. We found both lung-specific as well as systemic effects in immune parameters, metabolites, and lipids. Phytol drove modest changes in lung function and increased splenic CD4 T cell populations. We also conducted multi-omic data integration to better understand early complex pulmonary responses, highlighting a central enhancement of acetylcholine responses and downregulation of palmitic acid connected with conventional flow cytometric assessments of lung, systemic inflammation, and pulmonary function. Our results demonstrate that Ecig exposure not only leads to changes in pulmonary function but also affects systemic immune and metabolic parameters.
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Sistemas Electrónicos de Liberación de Nicotina , Animales , Multiómica , Pulmón , Glicerol , Vitamina E , Propilenglicol , AcetatosRESUMEN
The unfolded protein response (UPR) is associated with the risk of asthma, including treatment-refractory severe asthma. Recent studies demonstrated a pathogenic role of activating transcription factor 6a (ATF6a or ATF6), an essential UPR sensor, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by signal transducer and activator of transcription6 (STAT6) and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine secretion of TH2 and TH17 cells. T cell-specific Atf6-deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed the expression of ATF6 downstream genes and TH cell cytokines by both murine and human memory clusters of differentiation 4 (CD4)+ T cells. At the chronic stage of asthma, administration of Ceapin A7 lessened TH2 and TH17 responses, leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a critical role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma by targeting ATF6.
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Asma , Células Th2 , Ratones , Humanos , Animales , Células Th2/metabolismo , Asma/metabolismo , Granulocitos/metabolismo , Inflamación/metabolismo , Células Th17/metabolismo , Modelos Animales de Enfermedad , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismoRESUMEN
OBJECTIVE: Environmental exposures exacerbate age-related pathologies, such as cardiovascular and neurodegenerative diseases. Nanoparticulates, and specifically carbon nanomaterials, are a fast-growing contributor to the category of inhalable pollutants, whose risks to health are only now being unraveled. The current study assessed the exacerbating effect of age on multiwalled-carbon nanotube (MWCNT) exposure in young and old C57BL/6 and ApoE-/- mice. MATERIALS AND METHODS: Female C57BL/6 and apolipoprotein E-deficient (ApoE-/-) mice, aged 8 weeks and 15 months, were exposed to 0 or 40 µg MWCNT via oropharyngeal aspiration. Pulmonary inflammation, inflammatory bioactivity of serum, and neurometabolic changes were assessed at 24 h post-exposure. RESULTS: Pulmonary neutrophil infiltration was induced by MWCNT in bronchoalveolar lavage fluid in both C57BL/6 and ApoE-/-. Macrophage counts decreased with MWCNT exposure in ApoE-/- mice but were unaffected by exposure in C57BL/6 mice. Older mice appeared to have greater MWCNT-induced total protein in lavage fluid. BALF cytokines and chemokines were elevated with MWCNT exposure, but CCL2, CXCL1, and CXCL10 showed reduced responses to MWCNT in older mice. However, no significant serum inflammatory bioactivity was detected. Cerebellar metabolic changes in response to MWCNT were modest, but age and strain significantly influenced metabolite profiles assessed. ApoE-/- mice and older mice exhibited less robust metabolite changes in response to exposure, suggesting a reduced health reserve. CONCLUSIONS: Age influences the pulmonary and neurological responses to short-term MWCNT exposure. However, with only the model of moderate aging (15 months) in this study, the responses appeared modest compared to inhaled toxicant impacts in more advanced aging models.
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Nanotubos de Carbono , Femenino , Animales , Ratones , Nanotubos de Carbono/toxicidad , Ratones Endogámicos C57BL , Pulmón , Líquido del Lavado Bronquioalveolar , Inflamación/patología , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apolipoproteínas E/farmacología , Apolipoproteínas/metabolismo , Apolipoproteínas/farmacología , Exposición por Inhalación/efectos adversosRESUMEN
Utilizing a mobile laboratory located >300 km away from wildfire smoke (WFS) sources, this study examined the systemic immune response profile, with a focus on neuroinflammatory and neurometabolomic consequences, resulting from inhalation exposure to naturally occurring wildfires in California, Arizona, and Washington in 2020. After a 20-day (4 h/day) exposure period in a mobile laboratory stationed in New Mexico, WFS-derived particulate matter (WFPM) inhalation resulted in significant neuroinflammation while immune activity in the peripheral (lung, bone marrow) appeared to be resolved in C57BL/6 mice. Importantly, WFPM exposure increased cerebrovascular endothelial cell activation and expression of adhesion molecules (VCAM-1 and ICAM-1) in addition to increased glial activation and peripheral immune cell infiltration into the brain. Flow cytometry analysis revealed proinflammatory phenotypes of microglia and peripheral immune subsets in the brain of WFPM-exposed mice. Interestingly, endothelial cell neuroimmune activity was differentially associated with levels of PECAM-1 expression, suggesting that subsets of cerebrovascular endothelial cells were transitioning to resolution of inflammation following the 20-day exposure. Neurometabolites related to protection against aging, such as NAD+ and taurine, were decreased by WFPM exposure. Additionally, increased pathological amyloid-beta protein accumulation, a hallmark of neurodegeneration, was observed. Neuroinflammation, together with decreased levels of key neurometabolites, reflect a cluster of outcomes with important implications in priming inflammaging and aging-related neurodegenerative phenotypes.
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Contaminantes Atmosféricos , Incendios Forestales , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Animales , Células Endoteliales , Ratones , Ratones Endogámicos C57BL , Material Particulado/análisis , Material Particulado/toxicidad , Humo/efectos adversos , Estados UnidosRESUMEN
BACKGROUND: Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. RESULTS: C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1ß, IL-6, and TNF-α), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. CONCLUSIONS: Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.
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Nanotubos de Carbono , Neumonía , Animales , Líquido del Lavado Bronquioalveolar , Células Endoteliales , Ácidos Hidroxámicos , Pulmón , Inhibidores de la Metaloproteinasa de la Matriz/toxicidad , Ratones , Ratones Endogámicos C57BL , Nanotubos de Carbono/toxicidad , Neumonía/inducido químicamenteRESUMEN
Inhalation of tungsten particulates is a relevant route of exposure in occupational and military settings. Exposure to tungsten alloys is associated with increased incidence of lung pathologies, including interstitial lung disease and cancer. We have demonstrated, oral exposure to soluble tungsten enhances breast cancer metastasis to the lungs through changes in the surrounding microenvironment. However, more research is required to investigate if changes in the lung microenvironment, following tungsten particulate exposure, can drive tumorigenesis or metastasis to the lung niche. This study examined if inhalation to environmentally relevant concentrations of tungsten particulates caused acute damage to the microenvironment in the lungs and/or systemically using a whole-body inhalation system. Twenty-four female BALB/c mice were exposed to Filtered Air, 0.60 mg/m3, or 1.7 mg/m3 tungsten particulates (<1 µm) for 4 h. Tissue samples were collected at days 1 and 7 post-exposure. Tungsten accumulation in the lungs persisted up to 7 days post-exposure and produced acute changes to the lung microenvironment including increased macrophage and neutrophil infiltration, increased levels of proinflammatory cytokines interleukin 1 beta and C-X-C motif chemokine ligand 1, and an increased percentage of activated fibroblasts (alpha-smooth muscle actin+). Exposure to tungsten also resulted in systemic effects on the bone, including tungsten deposition and transient increases in gene expression of proinflammatory cytokines. Taken together, acute whole-body inhalation of tungsten particulates, at levels commonly observed in occupational and military settings, resulted in changes to the lung and bone microenvironments that may promote tumorigenesis or metastasis and be important molecular drivers of other tungsten-associated lung pathologies such as interstitial lung disease.
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Pulmón , Tungsteno , Administración por Inhalación , Animales , Polvo , Femenino , Exposición por Inhalación/efectos adversos , Pulmón/patología , Ratones , Infiltración Neutrófila , Tungsteno/metabolismo , Tungsteno/toxicidadRESUMEN
Particulate matter (PM) presents an environmental health risk for communities residing close to uranium (U) mine sites. However, the role of the particulate form of U on its cellular toxicity is still poorly understood. Here, we investigated the cellular uptake and toxicity of C-rich U-bearing particles as a model organic particulate containing uranyl citrate over a range of environmentally relevant concentrations of U (0-445 µM). The cytotoxicity of C-rich U-bearing particles in human epithelial cells (A549) was U-dose-dependent. No cytotoxic effects were detected with soluble U doses. Carbon-rich U-bearing particles with a wide size distribution (<10 µm) presented 2.7 times higher U uptake into cells than the particles with a narrow size distribution (<1 µm) at 100 µM U concentration. TEM-EDS analysis identified the intracellular translocation of clusters of C-rich U-bearing particles. The accumulation of C-rich U-bearing particles induced DNA damage and cytotoxicity as indicated by the increased phosphorylation of the histone H2AX and cell death, respectively. These findings reveal the toxicity of the particulate form of U under environmentally relevant heterogeneous size distributions. Our study opens new avenues for future investigations on the health impacts resulting from environmental exposures to the particulate form of U near mine sites.
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Uranio , Carbono , Carbón Mineral , Polvo/análisis , Humanos , Material Particulado/análisis , Material Particulado/toxicidad , Uranio/análisis , Uranio/toxicidadRESUMEN
Thromboembolic disorders are the leading cause of human mortality. Therefore, development of effective anticoagulant therapy is critical. Factor XIIIA (FXIIIA) protein is a crucial factor in the blood coagulation cascade, and hence it is a vital target for evolution of new antithrombotic agents. Structure-function studies of clotting factor active sites, clot formation, and thrombus structure have gained prominence in the efforts to develop novel anticoagulants. Factor XIIIA was homology modelled with the human transglutaminase-2 crystal structure as a base template for BLAST analysis. Docking and comparative binding site analysis revealed active site residue conservation and inhibitor-protein interactions. Nineteen small molecules possessing suspected anticoagulant properties were successfully docked into the FXIIIA active site following the best CoMFA and CoMSIA prediction values. Dabigatran etexilate was anticipated to be the best FXIIIA inhibitor among the nineteen anticoagulants with the highest binding affinity for the FXIIIA protein and the highest FlexX dock score of -29.8 KJ/mol. Structural properties of FXIIIA inhibitors with increased antithrombotic activity were predicted by this docking study.
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PURPOSE: To present the clinical data of 35 patients with T3 unresectable hepatocellular carcinoma (HCC) that were treated with (90)Y with the specific intent of downstaging to resection, radiofrequency ablation (RFA) candidate, United Network for Organ Sharing (UNOS) stage T2 or liver transplantation. MATERIALS AND METHODS: One hundred fifty patients with unresectable HCC were treated with (90)Y microspheres. Of these, 35 patients were UNOS stage T3 at the time of treatment. Patients were followed for clinical toxicities, alterations in model for end-stage-liver disease (MELD) score, tumor response, downstaging to RFA, resection, transplantation, and survival. RESULTS: Nineteen of 34 patients (56%) were successfully downstaged from T3 to T2 following treatment. 11 of 34 (32%) patients treated were downstaged to target lesions measuring 3.0 cm or less. Twenty-three of 35 (66%) were downstaged to either T2 status, lesion < 3.0 cm (RFA candidate), or resection. Seventeen of 34 (50%) had an objective tumor response by WHO criteria. Eight patients (23%) were successfully downstaged and underwent OLT following treatment. 1, 2, and 3-year survival was 84%, 54%, and 27%, respectively. Median survival by Kaplan-Meier analysis for the entire cohort was 800 days. CONCLUSION: These data suggest that intra-arterial (90)Y microspheres can be used as a bridge to transplantation, surgical resection, or RFA.
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Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/cirugía , Ablación por Catéter , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Microesferas , Anciano , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Terapia Combinada , Femenino , Arteria Hepática , Humanos , Infusiones Intraarteriales , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética , Masculino , Estadificación de Neoplasias , Radiometría , Tasa de Supervivencia , Tomografía Computarizada por Rayos X , Radioisótopos de Itrio/administración & dosificaciónRESUMEN
To present a critical review of yttrium-90 (TheraSphere) for the treatment of hepatocellular carcinoma (HCC). Medical literature databases (Medline, Cochrane Library, and CANCERLIT) were searched for available literature concerning the treatment of HCC with TheraSphere. These publications were reviewed for scientific and clinical validity. Studies pertaining to the use of yttrium-90 for HCC date back to the 1960s. The results from the early animal safety studies established a radiation exposure range of 50-100 Gy to be used in human studies. Phase I dose escalation studies followed, which were instrumental in delineating radiation dosimetry and safety parameters in humans. These early studies emphasized the importance of differential arteriolar density between hypervascular HCC and surrounding liver parenchyma. Current trends in research have focused on advancing techniques to safely implement this technology as an alternative to traditional methods of treating unresectable HCC, such as external beam radiotherapy, conformal beam radiotherapy, ethanol ablation, trans-arterial chemoembolization, and radiofrequency ablation. Yttrium-90 (TheraSphere) is an outpatient treatment option for HCC. Current and future research should focus on implementing multicenter phase II and III trials comparing TheraSphere with other therapies for HCC.
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Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Radioisótopos de Itrio/uso terapéutico , Embolización Terapéutica/métodos , Humanos , Microesferas , Dosificación Radioterapéutica , Radioisótopos de Itrio/administración & dosificaciónRESUMEN
In Canada and Europe, yttrium-90 microspheres (TheraSphere); MDS Nordion, Ottawa, Canada) are a primary treatment option for primary and secondary hepatic malignancies. We present data from 30 patients with hepatocellular carcinoma (HCC) and metastatic liver disease treated with TheraSphere from a single academic institution to evaluate the angiographically evident embolization that follows treatment. Seven interventional radiologists from one treatment center compared pretreatment and posttreatment angiograms. The reviewers were blinded to the timing of the studies. The incidence of postembolization syndrome (PES) was determined as well as objective tumor response rates by the World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), and European Association for the Study of the Liver (EASL) criteria. There were 420 independent angiographic observations that were assessed using the chi-squared statistic. The pretreatment and posttreatment angiograms could not be correctly identified on average more than 43% of the time (p = 0.0004). The postprocedure arterial patency rate was 100%. The objective tumor response rates for all patients were 24%, 31%, and 72% for WHO, RECIST, and EASL criteria, respectively. All of the patients tolerated the procedure without complications and were treated on an outpatient basis, and four patients had evidence of PES. This treatment method does not result in macroscopic embolization of the hepatic arteries, thereby maintaining hepatic tissue perfusion. These data support the principle that the favorable response rates reported with TheraSphere are likely due to radiation and microscopic embolization rather than flow-related macroscopic embolization and ischemia.