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A Muscarinic Antagonist Reduces Airway Inflammation and Bronchoconstriction Induced by Ambient Particulate Matter in a Mouse Model of Asthma.

ABSTRACT: Ambient particulate matter (PM) can increase airway inflammation and induce bronchoconstriction in asthma. This study aimed to investigate the effect of tiotropium bromide, a long-acting muscarinic antagonist, on airway inflammation and bronchoconstriction induced by ambient PM in a mouse model of asthma. We compared the effect of tiotropium bromide to that of fluticasone propionate and formoterol fumarate. BALB/c mice were sensitized to ovalbumin (OVA) via the airways and then administered tiotropium bromide, fluticasone propionate, or formoterol fumarate. Mice were also sensitized to ambient PM via intranasal instillation. Differential leukocyte counts and the concentrations of interferon (IFN)-γ, interleukin (IL)-5, IL-6, IL-13, and keratinocyte-derived chemokine (KC/CXCL1) were measured in bronchoalveolar lavage fluid (BALF). Diacron-reactive oxygen metabolites (dROMs) were measured in the serum. Airway resistance and airway inflammation were evaluated in lung tissue 24 h after the OVA challenge. Ambient PM markedly increased neutrophilic airway inflammation in mice with OVA-induced asthma. Tiotropium bromide improved bronchoconstriction, and reduced neutrophil numbers, decreased the concentrations of IL-5, IL-6, IL-13, and KC/CXCL1 in BALF. However, tiotropium bromide did not decrease the levels of dROMs increased by ambient PM. Though eosinophilic airway inflammation was reduced with fluticasone propionate, neutrophilic airway inflammation was unaffected. Bronchoconstriction was improved with formoterol fumarate, but not with fluticasone propionate. In conclusion, tiotropium bromide reduced bronchoconstriction, subsequently leading to reduced neutrophilic airway inflammation induced by ambient PM.

SUBMITTER: Kurai J

PROVIDER: S-EPMC6025324 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A Muscarinic Antagonist Reduces Airway Inflammation and Bronchoconstriction Induced by Ambient Particulate Matter in a Mouse Model of Asthma.

Kurai Jun J Watanabe Masanari M Sano Hiroyuki H Iwata Kyoko K Hantan Degejirihu D Shimizu Eiji E

International journal of environmental research and public health 20180606 6

Ambient particulate matter (PM) can increase airway inflammation and induce bronchoconstriction in asthma. This study aimed to investigate the effect of tiotropium bromide, a long-acting muscarinic antagonist, on airway inflammation and bronchoconstriction induced by ambient PM in a mouse model of asthma. We compared the effect of tiotropium bromide to that of fluticasone propionate and formoterol fumarate. BALB/c mice were sensitized to ovalbumin (OVA) via the airways and then administered tiot ...[more]

PMID: 29882826

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Project description:Murine Pulmonary Responses to Ambient Baltimore Particulate Matter: Genomic Analysis and Contribution to Airway Hyperresponsiveness Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Environmental factors such as ambient particulate matter (PM), a major air pollutant, has been demonstrated in epidemiological studies to contribute to asthma exacerbation and increased asthma prevalence. OBJECTIVE: We investigated the genomic and pathophysiological effects of Baltimore PM (median diameter 1.78 µm) in a murine model of asthma to identify potential biomarkers. METHODS: A/J mice with ovalbumin (OVA) –induced AHR were exposed to PM (20 mg/kg, intratracheal), and both AHR and bronchoalveolar lavage (BAL) were assayed on days 1, 4, and 7 post exposure. Lung gene expression profiling (Affymetrix Mouse430_ 2.0) by PM (20 mg/kg, intratracheal) were assayed on OVA- and / or PM--challenged mice. RESULTS: Significant increases of airway responsiveness in OVA-treated mice were observed, indicating an asthmatic phenotype. Ambient PM exposure induced significant changes in AHR in both naive mice and OVA-induced asthmatic mice. In both naive and OVA challenged asthmatic mice, PM induced eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of TH1 cytokines (IFN-g, IL-6, and TNF-a) and TH2 cytokines (IL-4, IL-5, and eotaxin) into BAL. Consistent with these results, PM induced expression of genes of innate immune response, chemotaxis and complementary system. CONCLUSION: These studies, consistent with epidemiological data, indicate that PM increases AHR and lung inflammation in naïve mice and exacerbates the asthma phenotype of increased AHR and gene expression pattern changes correlated with acute lung inflammation and airway damage. We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI. Keywords: gene expression

Project description:Endogenous redox systems not only counteract oxidative damage induced by high levels of hydroxyl radicals (OH·) under pathological conditions, but also shape redox signaling as a key player in the regulation of physiological processes. Second messengers like hydrogen peroxide and nitric oxide, as well as redox enzymes of the Thioredoxin (Trx) family, including Trxs, glutaredoxins (Grxs), and peroxiredoxins (Prxs) modulate reversible, oxidative modifications of proteins. Thereby redox regulation is part of various cellular processes such as the immune response and Trx proteins have been linked in different disorders including inflammatory diseases. Here, we have analyzed the protein distribution of representative oxidoreductases of the Trx fold protein family-Trx1, Grx1, Grx2, and Prx2-in a murine model of allergic asthma bronchiale, as well as their potential therapeutic impact on type-2 driven airway inflammation. Ovalbumin (OVA) sensitization and challenge using the type-2 prone Balb/c mouse strain resulted in increased levels of all investigated proteins in distinct cellular patterns. While concomitant treatment with Grx1 and Prx2 did not show any therapeutic impact on the outcome of the disease, Grx2 or Trx1 treatment before and during the OVA challenge phase displayed pronounced protective effects on the manifestation of allergic airway inflammation. Eosinophil numbers and the type-2 cytokine IL-5 were significantly reduced while lung function parameters profoundly improved. The number of macrophages in the bronchoalveolar lavage (BAL) did not change significantly, however, the release of nitric oxide that was linked to airway inflammation was successfully prevented by enzymatically active Grx2 ex vivo. The Grx2 Cys-X-X-Ser mutant that facilitates de-/glutathionylation, but does not catalyze dithiol/disulfide exchange lost the ability to protect from airway hyper reactivity and to decrease NO release by macrophages, however, it reduced the number of infiltrating immune cells and IL-5 release. Altogether, this study demonstrates that specific redox proteins and particular enzyme activities protect against inflammatory damage. During OVA-induced allergic airway inflammation, administration of Grx2 exerts beneficial and thus potentially therapeutic effects.

Project description:ImportanceFine particles (particulate matter 2.5 μm [PM2.5]), a ubiquitous air pollutant, can deposit in the small airways that play a vital role in asthma. It appears to be unknown whether the use of a PM2.5 filtration device can improve small airway physiology and respiratory inflammation in children with asthma.ObjectiveTo discover what pathophysiological changes in the small airways are associated with using a PM2.5-removing device in the bedrooms of children with asthma.Design, setting, and participantsChildren with mild or moderate asthma were enrolled in this double-blind, crossover study. The participants used a true filtration device and a sham filtration device in their bedrooms in a random order for 2 weeks each with a 2-week washout interval. The study was conducted in a suburb of Shanghai, China, during a low-ozone season.ExposuresOzone and PM2.5 were measured inside bedrooms and outside a window.Main outcomes and measuresImpulse oscillometry, spirometry, and fractional exhaled nitric oxide were measured at the beginning and the end of each intervention. Peak expiratory flow was measured twice daily at home.ResultsForty-three children (5-13 years old; 26 boys [60%]) participated. Outdoor 24-hour mean PM2.5 concentrations were moderately high, ranging from 28.6 to 69.8 μg/m3 (median, 53 μg/m3). During true filtration, bedroom PM2.5 concentrations were a mean (SD) of 63.4% (35.9%) lower than during sham filtration. Compared with sham filtration, true filtration was significantly associated with improved airway mechanics, reflected in a 24.4% (95% CI, 11.8%-37.1%) reduction in total airway resistance, a 43.5% (95% CI, 13.7%-73.3%) reduction in small airway resistance, a 22.2% (95% CI, 2.2%-42.2%) reduction in resonant frequency, and a 73.1% (95% CI, 0.3%-145.8%) increase in airway reactance. True filtration was also associated with significant improvements in fractional exhaled nitric oxide (a 27.6% [95% CI, 8.9%-42.4%] reduction) and peak expiratory flow (a 1.6% [95% CI, 0.8%-2.5%] increase). These improvements were significantly associated with bedroom PM2.5 reduction. Improvements in small airway function were nonsignificant (8.4% [95% CI, -1.4% to 18.3%]) in all participants but significant (13.2% [95% CI, 1.2%-25.1%]) in participants without eosinophilic airway inflammation at baseline. No improvements were observed for forced vital capacity, forced expiratory volume during the first second, and the ratio of these in all participants or subgroups.Conclusions and relevancePer these results, indoor PM2.5 filtration can be a practical method to improve air flow in an asthmatic lung through improved airway mechanics and function as well as reduced inflammation. This warrants a clinical trial to confirm.Trial registrationClinicalTrials.gov Identifier: NCT03282864.

Project description:BACKGROUND:Autoimmune diseases have increased in incidence and prevalence worldwide. While genetic predispositions play a role, environmental factors are a major contributor. Atmospheric particulate matter (PM) is a complex mixture composed of metals, nitrates, sulfates and diverse adsorbed organic compounds like polycyclic aromatic hydrocarbons (PAHs) and dioxins. Exposure to atmospheric PM aggravates autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, among others. PAHs and dioxins are known aryl hydrocarbon receptor (AHR) ligands. The AHR modulates T cell differentiation and directs the balance between effector and regulatory T cells in vitro and in experimental autoimmune encephalomyelitis (EAE), a murine model of autoimmune disease. This study aims to identify pathways that contribute to autoimmune disease and their potential use as therapeutic targets to alleviate symptoms and the need for global immunosuppression. This study tests the hypothesis that atmospheric PM enhances effector T cell differentiation and aggravates autoimmune disease. RESULTS:An atmospheric ambient urban dust PM sample, standard reference material (SRM)1649b, was tested for its effects on autoimmunity. SRM1649b PM enhanced Th17 differentiation in an AHR-dependent manner in vitro, however intranasal treatment of SRM1649b PM delayed onset of EAE and reduced cumulative and peak clinical scores. Chronic and acute intranasal exposure of SRM1649b PM delayed onset of EAE. Chronic intranasal exposure did not reduce severity of EAE while acute intranasal exposure significantly reduced severity of disease. Acute intranasal treatment of low dose SRM1649b PM had no effect on clinical score or day of onset in EAE. Delayed onset of EAE by intranasal SRM1649b PM was AHR-dependent in vivo. Oral gavage of SRM1649b PM, in the absence of AHR ligands in the diet, had no effect on day of disease onset or severity of EAE. Day 10 analysis of T cells in the CNS after intranasal treatment of SRM1649b PM showed a reduction of pathologic T cell subsets in vivo. Moreover, MOG-specific splenocytes require AHR to generate or maintain IL-10 producing cells and reduce IFN? producing cells in vitro. CONCLUSIONS:These results identify the AHR pathway as a potential target for driving targeted immunosuppression in the CNS in the context of atmospheric PM-mediated autoimmune disease. The effects of SRM1649b PM on EAE are dependent on route of exposure, with intranasal treatment reducing severity of EAE and delaying disease onset while oral gavage has no effect. Intranasal SRM1649b PM reduces pathologic T cells in the CNS, specifically Th1 cells and Th1Th17 double positive cells, leading to reduced severity of EAE and AHR-dependent delayed disease onset. Additionally, SRM1649b PM treatment of antigen-specific T cells leads to AHR-dependent increase in percent IL-10 positive cells in vitro. These findings may shed light on the known increase of infection after exposure to atmospheric PM and serve as the first step in identifying components of the AHR pathway responsible for Th1-mediated immunosuppression in response to atmospheric PM exposure.

Project description:Particulate matter (PM) is able to induce airway epithelial injury, while the detailed mechanisms remain unclear. Here we demonstrated that PM exposure inactivated MTOR (mechanistic target of rapamycin kinase), enhanced macroautophagy/autophagy, and impaired lysosomal activity in HBE (human bronchial epithelial) cells and in mouse airway epithelium. Genetic or pharmaceutical inhibition of MTOR significantly enhanced, while inhibition of autophagy attenuated, PM-induced IL6 expression in HBE cells. Consistently, club-cell-specific deletion of Mtor aggravated, whereas loss of Atg5 in bronchial epithelium reduced, PM-induced airway inflammation. Interestingly, the augmented inflammatory responses caused by MTOR deficiency were markedly attenuated by blockage of downstream autophagy both in vitro and in vivo. Mechanistically, the dysregulation of MTOR-autophagy signaling was partially dependent on activation of upstream TSC2, and interacted with the TLR4-MYD88 to orchestrate the downstream NFKB activity and to regulate the production of inflammatory cytokines in airway epithelium. Moreover, inhibition of autophagy reduced the expression of EPS15 and the subsequent endocytosis of PM. Taken together, the present study provides a mechanistic explanation for how airway epithelium localized MTOR-autophagy axis regulates PM-induced airway injury, suggesting that activation of MTOR and/or suppression of autophagy in local airway might be effective therapeutic strategies for PM-related airway disorders.Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; ALI: air liquid interface; AP2: adaptor related protein complex 2; ATG: autophagy related; BALF: bronchoalveolar lavage fluid; COPD: chronic obstructive pulmonary disease; CXCL: C-X-C motif chemokine ligand; DOX: doxycycline; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EPS15: epidermal growth factor receptor pathway substrate 15; HBE: human bronchial epithelial; H&E: hematoxylin & eosin; IKK: IKB kinase; IL: interleukin; LAMP2: lysosomal-associated membrane protein 2; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTEC: mouse tracheal epithelial cells; MTOR: mechanistic target of rapamycin kinase; MYD88: MYD88 innate immune signal transduction adaptor; NFKB: nuclear factor of kappa B; NFKBIA: NFKB inhibitor alpha; PM: particulate matter; PtdIns3K: phosphatidylinositol 3-kinase; Rapa: rapamycin; RELA: RELA proto-oncogene, NFKB subunit; SCGB1A1: secretoglobin family 1A member 1; siRNA: small interfering RNAs; SQSTM1: sequestosome 1; TEM: transmission electronic microscopy; TLR4: toll like receptor 4; TSC2: TSC complex subunit 2.

Dataset Information

A Muscarinic Antagonist Reduces Airway Inflammation and Bronchoconstriction Induced by Ambient Particulate Matter in a Mouse Model of Asthma.

Publications

A Muscarinic Antagonist Reduces Airway Inflammation and Bronchoconstriction Induced by Ambient Particulate Matter in a Mouse Model of Asthma.

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