Increased Airway Inflammation Research Articles

E3 Ubiquitin Ligase Cbl-b Inhibits Type 2 Innate Lymphoid Cell Development by Targeting ST2 for Ubiquitination

Abstract Type 2 innate lymphoid cells (ILC2) play a crucial role in driving allergic airway inflammation, but the regulation of ILC2 development is not fully understood. Previously we have shown that E3 ubiquitin ligase Cbl-b negatively regulates Th2 response, but whether Cbl-b also regulates ILC2-mediated type 2 immunity remains to be defined. In this study, we found that Rag1−/−Cblb−/− mice are hypersensitive to inhalation of A. Fumigatus, a fungus that causes allergic asthma, as revealed by heightened airway hyperresponsiveness (AHR), increased airway inflammation, and mucus production. This hypersensitivity is associated with increased frequencies of ILC2 and eosinophils, but reduced frequency of alveolar macrophages in the lungs. Consistent with this, type 2 cytokines are also increased in the lung homogenates of Rag1−/−Cblb−/− mice. At the molecular levels, ST2 undergoes ubiquitination and proteasome-mediated degradation upon IL-33 stimulation, which is abrogated in cells expressing Cbl-b C373A mutant. Therefore, our data indicate that Cbl-b inhibits the development of ILC2 and ILC2-mediated airway inflammation by targeting ST2 for ubiquitination.

Protective Effect of GHX02 Extract on Particulate Matter-Induced Lung Injury.

Industrial development, along with the rapid growth of the economy, has greatly improved the quality of life in humans. Moreover, advancements in medical technology have increased life expectancy. Small particles increase airway inflammation when they penetrate the alveoli. We observed that GHX02 decreased the frequency and delayed the onset time of citric acid-induced coughing in guinea pigs. A phenol red secretion assay indicated that the GHX02 extract exhibits potent expectorant activity. The GHX02 extract also greatly reduced leukocyte levels. Our results indicate that GHX02 inhibits airway inflammation, reduces sputum production, and relieves cough. The GHX02 extract suppressed histamine release from mast cells resulting from compound 48/80-induced degranulation. The extract exhibited antimicrobial activity against Streptococcus pneumoniae and significantly inhibited the formation of LTC4. At high concentrations, the GHX02 extract suppressed the formation of PGE2 (prostaglandin E2). Interleukin (IL)-4 and IL-13 levels decreased with an increasing dosage of GHX02. Oral administration of the GHX02 extract suppressed PM10D-induced inflammatory symptoms in the lung, including increased alveolar wall thickness, accumulation of collagen fibers, and cytokine release. Treatment with the GHX02 extract also resulted in lower levels of inflammatory cells, in bronchoalveolar lavage fluid and lung tissue. Our results indicate that GHX02 may be a useful therapeutic agent for treatment of respiratory diseases.

The Effect of Administration of Lycopene on Interleukin 8 Levels and Hospitalization Time of Patients with Chronic Obstructive Pulmonary Disease Exacerbations

Background: Exacerbated chronic obstructive pulmonary disease is an acute condition, characterized by persistent air flow limitations, related to the excessive chronic inflammatory response in the airways and lung parenchyma caused by exposure to harmful gases or particles. Increased airway inflammation during exacerbations leads to increased levels of IL-8 and the risk of hospitalization. Lycopene is a carotenoid which has a positive effect on the respiratory system. The purpose of this study was to determine the effect of administration lycopene to IL-8 levels and hospitalization time of patients with COPD disease exacerbations.Methods: The experimental test with pretest and posttest design for 30 patients with COPD exacerbations in Dr. Moewardi Surakarta Hospital and Dr. Soehadi Prijonegoro Sragen Hospital was conducted from February to March 2018. Samples were taken by consecutive sampling divided into two groups including the treatment group receiving standard therapy and lycopene 1x10 mg / day during treatment and the control group only receiving standard therapy. IL-8 levels and hospitalization time of patients with COPD disease exacerbations were measured.Results: There were significant differences between the treatment group compared to the control group for a decrease in IL-8 (p = 0.029) and a decrease in hospitalization time (p = 0,000).Conclusion: The administration of lycopene 1x10 mg / day significantly reduce IL-8 levels and hospitalization time of patient with COPD exacerbations.

Variability in airway inflammation, symptoms, lung function and reliever use in asthma: anti-inflammatory reliever hypothesis and STIFLE study design.

Asthma is a chronic inflammatory airway disease. Increase in airway inflammation is hypothesised to contribute to worsening of asthma symptoms and deterioration in lung function, resulting in the use of reliever medication. Short-acting β2-agonists only treat the symptoms, whereas an anti-inflammatory reliever is believed to treat both symptoms and the underlying inflammation, thereby arresting the progression to an exacerbation. As-needed budesonide/formoterol as an anti-inflammatory reliever reduces the risk of severe exacerbations. However, supporting mechanistic evidence has not yet been described, specifically the temporal dynamics of parameters including airway inflammation, over time and during asthma worsening.The STIFLE study aims to characterise daily variability in airway inflammation, symptoms, lung function and reliever use in people with asthma. This phase IV, open-label, parallel-group, multicentre, exploratory study will enrol 60–80 adult patients with asthma receiving low- or medium-dose inhaled corticosteroids/long-acting β2-agonists (EudraCT identifier number 2018-003467-64). Participants will be randomised 1:1 to either as-needed budesonide/formoterol dry-powder inhaler or salbutamol reliever for 24 weeks, in addition to their maintenance therapy. Daily data will be captured for fractional exhaled nitric oxide, spirometry, asthma symptoms and medication use using devices connected to a smartphone via the STIFLE application. STIFLE will thereby enable not only characterisation of the variability of airway inflammation and clinical outcomes in relation to asthma worsening, but also elucidate the effect of as-needed budesonide/formoterol on airway inflammation against a background of daily maintenance therapy.

The effect of administration of lycopene on interleukin 8 levels and hospitalization time of patients with chronic obstructive pulmonary disease exacerbations

Abstrak. Latar Belakang: Eksaserbasi pada penyakit paru obstruktif kronik merupakan kondisi akut yang ditandai dengan hambatan aliran udara yang persisten dari respon inflamasi kronik yang berlebihan pada saluran napas dan parenkim paru yang disebabkan oleh paparan gas atau partikel berbahaya. Peningkatan peradangan saluran napas selama eksaserbasi menyebabkan peningkatan kadar IL-8 dan risiko rawat inap. Likopen merupakan karotenoid yang memiliki efek positif pada sistem pernapasan. Tujuan penelitian ini adalah untuk mengetahui pengaruh pemberian likopen terhadap kadar IL-8 dan lama rawat inap pasien PPOK eksaserbasi akut.Metode: Uji eksperimental dengan desain pretest dan posttest pada 30 pasien PPOK eksaserbasi di RSUD Dr. Moewardi, Surakarta dan RSUD Dr. Soehadi Prijonegoro, Sragen dilakukan pada bulan Februari-Maret 2018. Pengambilan sampel secara consecutive sampling dibagi menjadi dua kelompok yaitu kelompok perlakuan yang mendapat terapi standar dan likopen 1x10 mg/hari selama pengobatan dan kelompok kontrol hanya mendapat terapi standar. Dilakukan pengukuran kadar IL-8 dan waktu rawat inap pasien dengan PPOK eksaserbasi.Hasil: Terdapat perbedaan yang bermakna antara kelompok perlakuan dibandingkan dengan kelompok kontrol untuk penurunan IL-8 (p = 0,029) dan penurunan waktu rawat inap (p = 0,000).Kesimpulan: Pemberian likopen 1x10 mg / hari secara signifikan menurunkan kadar IL-8 dan lama rawat inap pasien eksaserbasi PPOK.Kata kunci: eksaserbasi akut, kadar IL-8, lama rawat inap, likopen, PPOK.Abstract. Background: Exacerbated chronic obstructive pulmonary disease is an acute condition, characterized by persistent air flow limitations, related to the excessive chronic inflammatory response in the airways and lung parenchyma caused by exposure to harmful gases or particles. Increased airway inflammation during exacerbations leads to increased levels of IL-8 and the risk of hospitalization. Lycopene is a carotenoid which has a positive effect on the respiratory system. The purpose of this study was to determine the effect of administration lycopene to IL-8 levels and hospitalization time of patients with COPD disease exacerbations.Methods: The experimental test with pretest and posttest design for 30 patients with COPD exacerbations in Dr. Moewardi Surakarta Hospital and Dr. Soehadi Prijonegoro Sragen Hospital was conducted from February to March 2018. Samples were taken by consecutive sampling divided into two groups including the treatment group receiving standard therapy and lycopene 1x10 mg / day during treatment and the control group only receiving standard therapy. IL-8 levels and hospitalization time of patients with COPD disease exacerbations were measured.Results: There were significant differences between the treatment group compared to the control group for a decrease in IL-8 (p = 0.029) and a decrease in hospitalization time (p = 0,000).Conclusion: The administration of lycopene 1x10 mg / day significantly reduce IL-8 levels and hospitalization time of patient with COPD exacerbations.Keywords: lycopene, COPD, acute exacerbation, IL-8 level, hospitalization time

Relationship between Particulate Matter (PM10) and Airway Inflammation Measured with Exhaled Nitric Oxide Test in Seoul, Korea.

Purpose Particulate matter (PM) is increasing every year in Asia. It is not fully understood how the airway is affected when inhaling PM. We investigated the correlation between particulate matter with a diameter of less than 10 μm (PM10) and fractional exhaled nitric oxide (FeNO) to determine whether PM causes airway inflammation. Material and Methods. We analyzed patients who visited our outpatient clinic and tested FeNO from January 2016 to December 2017 at the Korea University Guro Hospital. PM10 data were provided by the government of the Republic of South Korea, and measuring station of PM10 is located 800 meters from the hospital. We analyzed the correlation between PM10 and FeNO by a Pearson correlation analysis and by a multivariate linear regression analysis. To identify the most correlated times, we analyzed the correlation between the FeNO and PM10 daily average from the day of visit to 4 days before visit. Results FeNO positively correlated with PM10 at two days before hospital visit in the Pearson correlation (Pearson correlation coefficient = 0.057; P-value = 0.023) and in the multivariate linear regression analysis (B = 0.051, P-value = 0.026). If the PM10 increased by 100 μg/m3, the FeNO result was expected to rise to 8.3 ppb in healthy people without respiratory disease. Conclusion The positive correlation was found in both healthy people and asthmatic patients. Therefore, PM10 can increase airway inflammation.

Evaluation of Interleukin-6, Leukotriene B-4, and Nitric Oxide Levels in Exhaled Breath Condensate of Asymptomatic Obese Individuals: Are Obese Patients Under Risk of Developing Asthma?

If systemic inflammation in relation with obesity causes asthma, the detection of increased airway inflammation among obese individuals who do not have any respiratory symptoms can be also beneficial in indentifying obese patients who are at risk of developing asthma. The aim of this study was to evaluate the systemic and airway inflammation of asymptomatic obese and non-obese individuals. Obese and non-obese individuals with no respiratory symptoms were included. Inflammatory biomarkers such as C-reactive protein (CRP), exhaled breath condensate (EBC) interleukin-6 (IL-6), EBC leukotriene B-4 (LTB-4), and EBC nitric oxide (NO) levels of obese and non-obese individuals were determined. Forty-five obese individuals (body mass index [BMI]≥30) and 31 non-obese individuals (BMI≤25) as a control group were included in this study. The mean age of the obese group (38.7±11.4 years) was significantly higher than the one of the non-obese group (29.5±8.6 years; p<0.001). There was no significant relationship between gender and BMI (χ2 =1.471, p=0.225). CRP levels were significantly higher in the obese group (6.94±8.28) than the non-obese group (3.29±0.39; p<0.001). The levels of EBC IL-6 in obese and non-obese group were found as 22.61±12.53 and 21.08±14.39, respectively (p=0.624). There was no significant difference between EBC NO levels of the obese group and non-obese group (24.35±10.9 vs. 21.56±7.83; p=0.226). No significant difference was found between the EBC LTB-4 level in the obese group and the non-obese group (36.39±89.82 vs. 16.64±17.45; p=0.231). Increased systemic inflammation in obese individuals who had no respiratory symptoms might indicate the tendency of asthma. However, airway inflammation was not significantly different between groups. Therefore the relationship between obesity and asthma should be investigated in future large-scale studies determining the direct effects of adipokines on airways.

Thymic stromal lymphopoietin protects in a model of airway damage and inflammation via regulation of caspase-1 activity and apoptosis inhibition

Thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine, exhibits both pro-inflammatory and pro-homeostatic properties depending on the context and tissues in which it is expressed. It remains unknown whether TSLP has a similar dual role in the airways, where TSLP is known to promote allergic inflammation. Here we show that TSLP receptor (TSLPR)-deficient mice (Tslpr−/−) and mice treated with anti-TSLP antibodies exhibited increased airway inflammation and morbidity rates after bleomycin-induced tissue damage. We found that signaling through TSLPR on non-hematopoietic cells was sufficient for TSLP’s protective function. Consistent with this finding, we showed that TSLP reduces caspase-1 and caspase-3 activity levels in primary human bronchial epithelial cells treated with bleomycin via Bcl-xL up-regulation. These observations were recapitulated in vivo by observing that Tslpr−/− mice showed reduced Bcl-xL expression that paralleled increased lung caspase-1 and caspase-3 activity levels and IL-1β concentrations in the bronchial-alveolar lavage fluid. Our studies reveal a novel contribution for TSLP in preventing damage-induced airway inflammation.

Respiratory Viral Infections in Exacerbation of Chronic Airway Inflammatory Diseases: Novel Mechanisms and Insights From the Upper Airway Epithelium.

Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.

Establishment of a mouse model mimicking neutrophilic steroid-refractory asthma

Objective To establish a murine model of neutrophilic steroid-refractory asthma for a better exploration of its pathogenesis and treatment. Methods A mouse model of neutrophilic steroid-refractory asthma was established by intratracheal administration of a mixture of house dust mite (HDM) and lipopolysaccharide (LPS). Eighteen female C57BL/6 mice were randomly divided into a control group, an asthma group (HDM+LPS) and a dexamethasone (Dex) group (HDM+LPS+Dex). The airway resistance was measured by pulmonary function test. Airway inflammation, hypersecretion and inflammatory cell recruitment were observed by HE, PAS and Wright′s staining, respectively. Inflammatory mediators in lung and bronchoalveolar lavage fluid (BALF) were detected by PCR and ELISA. Th17 cell differentiation in the lung was analyzed by flow cytometry. Results HE staining showed a significantly increased airway inflammation in the asthma group than that in the control group (P 0.05). Cell counts in BALF showed a sharply elevated recruitment of inflammatory cells in the asthma group (except eosinophils) than that in the control group (total number of inflammatory cells (2797±400)×106/L vs (105±75)×106/L, neutrophils (1151±395)×106/L vs (12±6)×106/L, lymphocytes(897±135)×106/L vs (11±5)×106/L, macrophages (215±51)×106/L vs (34±16)×106/L, P 0.05]. Immunohistochemical staining confirmed that Dex could not effectively alleviate the neutrophilic inflammation in asthmatic mice. Although there was no significant difference in airway hyperreactivity between the asthma group and the Dex group (P>0.05), both had a higher airway hyperreactivity than that of the control group (P<0.05). The Dex group exhibited a significantly lower Th2-related inflammatory mediators in the lung than the asthma group (all P<0.05), together with an increased trend in Th17 cell-related inflammatory mediators and no improvement in Th1-related inflammatory mediators. Flow cytometry showed an obviously increased percentage of Th17 cells in the Dex group than that in the asthma group [(5.8±1.9)% vs (2.3±0.8)%, P<0.01]. Conclusion A novel murine model mimicking clinical neutrophilic asthma was elegantly established, in which Dex could not attenuate the neutrophilic airway inflammation and hyperreactivity, but rather augmented Th17 cell differentiation, demonstrating the presence of steroid-resistance. Key words: Asthma; Dexamethasone; Neutrophils; Th17 cells

Infection prevention and chronic disease management in cystic fibrosis and noncystic fibrosis bronchiectasis.

Bronchiectasis is a chronic lung disease (CLD) characterized by irreversible bronchial dilatation noted on computed tomography associated with chronic cough, ongoing viscid sputum production, and recurrent pulmonary infections. Patients with bronchiectasis can be classified into two groups: those with cystic fibrosis and those without cystic fibrosis. Individuals with either cystic fibrosis related bronchiectasis (CFRB) or noncystic fibrosis related bronchiectasis (NCFRB) experience continuous airway inflammation and suffer airway architectural changes that foster the acquisition of a unique polymicrobial community. The presence of microorganisms increases airway inflammation, triggers pulmonary exacerbations (PEx), reduces quality of life (QOL), and, in some cases, is an independent risk factor for increased mortality. As there is no cure for either condition, prevention and control of infection is paramount. Such an undertaking incorporates patient/family and healthcare team education, immunoprophylaxis, microorganism source control, antimicrobial chemoprophylaxis, organism eradication, daily pulmonary disease management, and, in some cases, thoracic surgery. This review is a summary of recommendations aimed to thwart patient acquisition of pathologic organisms, and those therapies known to mitigate the effects of chronic airway infection. A thorough discussion of airway clearance techniques and treatment of or screening for nontuberculous mycobacteria (NTM) is beyond the scope of this discussion.

Exchange protein directly activated by cAMP (Epac) protects against airway inflammation and airway remodeling in asthmatic mice

Backgroundβ2 receptor agonists induce airway smooth muscle relaxation by increasing intracellular cAMP production. PKA is the traditional downstream signaling pathway of cAMP. Exchange protein directly activated by cAMP (Epac) was identified as another important signaling molecule of cAMP recently. The role of Epac in asthmatic airway inflammation and airway remodeling is unclear.MethodsWe established OVA-sensitized and -challenged acute and chronic asthma mice models to explore the expression of Epac at first. Then, airway inflammation and airway hyperresponsiveness in acute asthma mice model and airway remodeling in chronic asthma mice model were observed respectively after treatment with Epac-selective cAMP analogue 8-pCPT-2′-O-Me-cAMP (8pCPT) and Epac inhibitor ESI-09. Next, the effects of 8pCPT and ESI-09 on the proliferation and apoptosis of in vitro cultured mouse airway smooth muscle cells (ASMCs) were detected with CCK-8 assays and Annexin-V staining. Lastly, the effects of 8pCPT and ESI-09 on store-operated Ca2+ entry (SOCE) of ASMCs were examined by confocal Ca2+ fluorescence measurement.ResultsWe found that in lung tissues of acute and chronic asthma mice models, both mRNA and protein expression of Epac1 and Epac2, two isoforms of Epac, were lower than that of control mice. In acute asthma mice model, the airway inflammatory cell infiltration, Th2 cytokines secretion and airway hyperresponsiveness were significantly attenuated by 8pCPT and aggravated by ESI-09. In chronic asthma mice model, 8pCPT decreased airway inflammatory cell infiltration and airway remodeling indexes such as collagen deposition and airway smooth muscle cell proliferation, while ESI-09 increased airway inflammation and airway remodeling. In vitro cultured mice ASMCs, 8pCPT dose-dependently inhibited, whereas ESI-09 promoted ASMCs proliferation. Interestingly, 8pCPT promoted the apoptosis of ASMCs, whereas ESI-09 had no effect on ASMCs apoptosis. Lastly, confocal Ca2+ fluorescence examination found that 8pCPT could inhibit SOCE in ASMCs at 100 μM, and ESI-09 promoted SOCE of ASMCs at 10 μM and 100 μM. In addition, the promoting effect of ESI-09 on ASMCs proliferation was inhibited by store-operated Ca2+ channel blocker, SKF-96365.ConclusionsOur results suggest that Epac has a protecting effect on asthmatic airway inflammation and airway remodeling, and Epac reduces ASMCs proliferation by inhibiting SOCE in part.

Effect of industrial point-source air pollutants on fractional exhaled nitric oxide in healthy volunteers

BackgroundFew studies have examined the effects of industrial, fixed-site sources of air pollution on lung inflammation in nearby residents. We investigated the effects of short-term exposure to ambient air near a steel plant on the fractional exhaled concentration of nitric oxide (FeNO), a measure of airway inflammation, in healthy volunteers. MethodsA cross-over study design was used. Fifty-nine non-smoking participants (mean age 24 years) were randomly assigned to each of two 5-day exposure scenarios: breathing ambient air adjacent to a steel plant or 5 km away at a college campus site. FeNO and on-site air pollutants were measured daily. Mixed effects linear regression models were used for data analysis, adjusting for sex, temperature, humidity and day of week. ResultsCompared with the college site, PM 2.5, ultrafine PM, SO2, NO2 and CO levels were significantly greater near the steel plant. FeNO was 15.3% (95% CI, 6.6%, 24.8%) higher near the plant compared to the college site. ConclusionsExposure to ambient air near a steel plant was associated with increased airway inflammation as measured by exhaled nitric oxide.

The modification of three vulnerability theories to assist nursing practice for school-age children with severe asthma.

Severe asthma is an inflammatory illness associated with adverse health outcomes and behaviors in children, such as decreased quality of life, impaired sleep, and increased medical costs and morbidity. Children with severe asthma frequently exhibit a cycle of health and behaviors which contribute to these adverse health outcomes, consisting of decreased physical activity, increased stress, and increased airway inflammation and asthma exacerbations. School-age children, in particular, are a vulnerable population because they not only rely on others for their care but also suffer from a chronic illness and are at risk for unequal healthcare access and health outcomes. Currently, there is no one nursing theory that adequately addresses the vulnerability, cycle of health and behaviors, and adverse health outcomes of children with severe asthma. By integrating key concepts from three vulnerability theories and presenting a modified conceptual framework, this paper aims to demonstrate how the use of this new conceptual framework may assist nurses in evaluating the unique needs of school-age children with severe asthma to provide best practices and develop appropriate interventions.

Transcriptional Profiling of the Murine Airway Response to Acute Ozone Exposure.

Ambient ozone (O3) exposure has serious consequences on respiratory health, including airway inflammation and injury. Decades of research have yielded thorough descriptions of these outcomes; however, less is known about the molecular processes that drive them. The aim of this study was to further describe the cellular and molecular responses to O3 exposure in murine airways, with a particular focus on transcriptional responses in 2 critical pulmonary tissue compartments: conducting airways (CA) and airway macrophages (AM). After exposing adult, female C57BL/6J mice to filtered air, 1 or 2 ppm O3, we assessed hallmark responses including airway inflammation (cell counts and cytokine secretion) and injury (epithelial permeability), followed by gene expression profiling of CA and AM by RNA-seq. As expected, we observed concentration-dependent increases in airway inflammation and injury. Conducting airways and AM both exhibited changes in gene expression to both 1 and 2 ppm O3 that were largely compartment-specific. In CA, genes associated with epithelial barrier function, detoxification processes, and cellular proliferation were altered, while O3 affected genes involved in innate immune signaling, cytokine production, and extracellular matrix remodeling in AM. Further, CA and AM also exhibited notable differences in concentration-response expression patterns for large numbers of genes. Overall, our study has described transcriptional responses to acute O3 exposure, revealing both shared and unique gene expression patterns across multiple concentrations of O3 and in 2 important O3-responsive tissues. These profiles provide broad mechanistic insight into pulmonary O3 toxicity, and reveal a variety of targets for focused follow-up studies.

The Effect of Flavored E-cigarettes on Murine Allergic Airways Disease

Flavored e-cigarettes are preferred by the majority of users yet their potential toxicity is unknown. Therefore our aim was to determine the effect of selected flavored e-cigarettes, with or without nicotine, on allergic airways disease in mice. Balb/c mice were challenged with PBS or house dust mite (HDM) (Days 0, 7, 14–18) and exposed to room air or e-cigarette aerosol for 30 min twice daily, 6 days/week from Days 0–18 (n = 8–12/group). Mice were exposed to Room Air, vehicle control (50%VG/%50PG), Black Licorice, Kola, Banana Pudding or Cinnacide without or with 12 mg/mL nicotine. Mice were assessed at 72 hours after the final HDM challenge. Compared to mice challenged with HDM and exposed to Room Air, nicotine-free Cinnacide reduced airway inflammation (p = 0.045) and increased peripheral airway hyperresponsiveness (p = 0.02), nicotine-free Banana Pudding increased soluble lung collagen (p = 0.049), with a trend towards increased airway inflammation with nicotine-free Black Licorice exposure (p = 0.089). In contrast, all e-cigarettes containing nicotine suppressed airway inflammation (p < 0.001 for all) but did not alter airway hyperresponsiveness or airway remodeling. Flavored e-cigarettes without nicotine had significant but heterogeneous effects on features of allergic airways disease. This suggests that some flavored e-cigarettes may alter asthma pathophysiology even when used without nicotine.

Effects of nanoparticles on neuroinflammation in a mouse model of asthma

The interaction between chronic inflammation and neural dysfunction points to a link between the nervous and immune systems in the airways. In particular, environmental exposure to nanoparticles (NPs), defined as particulate matter having one dimension <100 nm, is associated with an enhanced risk of childhood and adult asthma. However, the impact of NPs on the neural response in asthma remains to be determined.This study determined the impact of NPs on neuroinflammation in a mouse model of allergic asthma.Ovalbumin (OVA) sensitized mice were treated with saline (Sham), OVA challenged and exposed to 200 μg/m3 NPs 1 h a day for 3 days on days 21–23 in a closed-system chamber attached to a ultrasonic nebulizer. The effect of NPs on the levels of neuropeptides, transient receptor potential vanilloid 1 (TRPV1), TRPV4, P2 × 4, and P2 × 7 was assessed by enzyme-linked immunosorbent assays, immunoblotting, and immunohistochemistry.NP exposure increased airway inflammation and responsiveness in OVA mice, and these increases were augmented in OVA plus NP-exposed mice. The lung tissue levels of TRPV1, TRPV4, P2 × 4, and P2 × 7 were increased in OVA mice, and these increases were augmented in OVA plus NP-exposed mice. The substance P, adenosine triphosphate (ATP), and calcitonin gene-related peptide (CGRP) levels in bronchoalveolar lavage fluid were increased in OVA mice, and these increases were augmented in OVA plus NP-exposed mice. Bradykinin, ATP, and CGRP were dose dependently increased in NP-exposed normal human bronchial epithelial (NHBE) cells. The calcium concentration was increased in NHBE cells exposed to NPs for 8 h.These results indicate that neuroinflammation can be involved in the pathogenesis of bronchial asthma and that NPs can exacerbate asthma via neuromediator release.

Outdoor fungal spores and acute respiratory effects in vulnerable individuals

BackgroundMany outdoor fungal spores are ubiquitous, respirable and possibly allergenic. They may contribute to asthma symptoms; however, little is known about their effects on respiratory function. ObjectiveTo investigate if outdoor fungal spore levels were associated with lung function or airway inflammation, and whether fungal sensitization or current asthma modified any associations. MethodsCross-sectional associations between same day (Lag0) and cumulative 3-day lagged (Lag0-3) counts of 12 outdoor fungal spore taxa and pre-bronchodilator spirometry (FEV1, FVC, FEF25%–75%), bronchodilator response (BDR) and airway inflammation (fractional exhaled nitric oxide (FeNO) and exhaled breath condensate (EBC) nitrogen oxides (NOx) and pH were investigated in 936 Melbourne Atopy Cohort Study participants during September 2009 to December 2011. Generalized linear models were used to quantify associations with lung function, FeNO and EBC pH; generalized estimating equations for BDR; and ordinal logistic regression for EBC NOx. Models were adjusted for age, sex, height, temperature, relative humidity, grass pollen and sample storage time. Potential effect modification by fungal sensitization and current asthma were examined using interaction terms. ResultsMixed associations were found. Higher levels of Ustilago/smuts were associated with lower lung function at Lag0 (FEV1: 21ml [95%CI -36, −7]; FEF25%–75%: 39ml [-65, −13]) and Lag0-3 (FEV1: 9ml [-14, −4]; FEF25%–75% −18ml [-27, −9]). Positive BDR was associated with Ustilago/smuts (Lag0 OR = 1.1 [1.04, 1.2]; Lag0-3 OR = 1.04 [1.02, 1.07]), Alternaria (Lag0 OR = 1.3 [1.0, 1.6]) and Drechslera (Lag0 OR = 1.1 [1.03, 1.2]). Higher EBC NOx was associated with Cladosporium (Lag0-3 OR = 1.1 [1.0, 1.2]), Alternaria (Lag0-3 OR = 1.1 [1.0, 1.3]). No associations were found with higher FeNO. In those with fungal sensitization, Ustilago/smuts and Drechslera were associated with lower FEV1 and FVC; Cladosporium was associated with increased FEV1, FVC and FEF25%–75% but also with higher FeNO and lower EBC pH. In those with current asthma, Alternaria, Ustilago/smuts and Drechslera were associated with lower FEV1, FVC, FEF25–75% and EBC pH. ConclusionExposure to outdoor fungal spores may be associated with lower lung function and increased airway inflammation, particularly in those with fungal sensitization and/or current asthma.

Urinary arsenic concentration, airway inflammation, and lung function in the U.S. adult population

BackgroundInorganic arsenic (iAs) is ubiquitous in the environment and has been linked to lung cancer and a number of non-malignant lung disease in both adults and children. However, most studies were conducted in populations with higher arsenic exposure levels in drinking water and relatively little epidemiologic research evaluated the impacts of low levels iAs exposure on non-malignant lung disease among populations that are not primarily exposed to arsenic through drinking water. ObjectivesWe assessed the associations of arsenic exposure with airway inflammation and lung function among U.S. adults aged 20–79 years using data from the National Health and Nutrition Examination Survey 2007–2012 cycles. MethodsTwo measures of arsenic exposure, urinary total arsenic and dimethylarsonic acid (DMA), were used. We calibrated these two exposure measures by regressing their concentrations by arsenobetaine and extracting the residuals to calculate estimated total arsenic and estimated DMA. Arsenic exposures were modeled as log-transformed continuous variables as well as quartile categories. Fractional exhaled nitric oxide (FENO), an indicator of respiratory inflammation, was available for participants. For lung function, the best forced expiratory volume in the first one second (FEV1), forced vital capacity (FVC), forced expiratory flow rate (FEF) 25–75%, their percent estimated values, ratios of FEV1 to FVC, and FEF 25–75% to FVC were used (i.e. FEV1/FVC and FEF/FVC). Weighted multivariable linear regression models, adjusted for potential confounders, were used to evaluate the association of arsenic exposure with airway inflammation and lung function overall, and among males and females. ResultsSignificant associations between arsenic exposure and increased airway inflammation were found. A two-fold increase in urinary total arsenic and DMA was associated with 23.87% (95% CI: 2.66, 49.46) and 14.05% (95% CI: 1.77, 27.81) higher levels of FENO, respectively. In addition, participants in the highest quartile of urinary total arsenic had FENO levels 8.49% (95% CI: 1.13, 16.39) higher than those in the lowest quartile. These associations were similar between males and females. Limited evidence was found for the association with respect to lung function and potential modification effect of sex. ConclusionsArsenic exposure was related to increased risk of airway inflammation but there is limited evidence of an association in relation to lung function. Future research conducted in populations with relatively lower exposure levels that are not primarily exposed to arsenic through drinking water is needed to confirm our findings.

The alpha-melanocyte-stimulating hormone acts as a local immune homeostasis factor in experimental allergic asthma.

Originally, the neuropeptide α-melanocyte-stimulating hormone (α-MSH) has been described as a mediator of skin pigmentation. However, recent studies have shown that α-MSH is able to modulate inflammation in various tissues including the lung. So far, it is still not clear whether α-MSH also plays a role in allergic bronchial asthma. This study aimed at investigating the role and regulatory mechanisms of α-MSH in asthma pathogenesis. α-MSH levels were measured in bronchoalveolar lavage (BAL) fluid of asthmatic and non-asthmatic individuals as well as of healthy mice and mice with experimental asthma. Wild-type mice were sensitized to ovalbumin (OVA) and exposed to an OVA aerosol in order to induce experimental allergic asthma. α-MSH was administrated intratracheally, the α-MSH antibody intraperitoneally prior each OVA challenge. Airway inflammation, cytokine production, mucus production, airway hyperresponsiveness and receptor expression were assessed. α-MSH levels in BAL of asthmatic individuals and mice were significantly higher compared to healthy controls. In a mouse model of experimental asthma, α-MSH neutralization increased airway inflammation and mucus production, whereas local administration of α-MSH significantly reduced inflammation of the airways. The beneficial effects were further associated with decreased levels of eosinophilic chemoattractant factors that are released by MC5R-positive T helper 2 and airway epithelial cells. α-MSH acts as a regulatory factor to maintain local immune homeostasis in allergic bronchial asthma.