It has been recently that particulate matter (PM) exposure increases the risk and exacerbation of allergic asthma. However, the underlying mechanisms and factors associated with increased allergic ...responses remain elusive. We evaluated IL‐23 and IL‐23R (receptor) expression, as well as changes in the asthmatic phenotype in mice administered PM and a low dose of house dust mite (HDM). Next, changes in the phenotype and immune responses were evaluated after intranasal administration of anti‐IL‐23 antibody during co‐exposure to PM and low‐dose HDM. We also performed in vitro experiments to investigate the effect of IL‐23. IL‐23 expression was significantly increased in Epcam+CD45− and CD11c+ cells, while that of IL‐23R was increased in Epcam+CD45− cells only in mice administered PM and low‐dose HDM. Administration of anti‐IL‐23 antibody led to decreased airway hyperresponsiveness, eosinophils, and activation of dendritic cells, reduced populations of Th2 Th17, ILC2, the level of IL‐33 and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Inhibition of IL‐23 in PM and low‐dose HDM stimulated airway epithelial cell line resulted in decreased IL‐33, GM‐CSF and affected ILC2 and the activation of BMDCs. PM augmented the phenotypes and immunologic responses of asthma even at low doses of HDM. Interestingly, IL‐23 affected immunological changes in airway epithelial cells.
We aimed to investigate the differences in interleukin (IL)-10, IL-1β, IL-6, and tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated CD14++CD16+ monocytes obtained from ...asthmatics after dexamethasone or dexamethasone plus rapamycin treatments between clinical steroid responders (R) and non-responders (NR).
Cytokine expressions in LPS-stimulated CD14++CD16+ p-mammalian target of rapamycin (mTOR) monocytes from R and NR were determined using flow cytometry.
IL-10
CD14++CD16+ p-mTOR population following LPS stimulation increased in the R group although decreased in the NR group with dexamethasone treatment. IL-1β
population decreased in the R group although increased in the NR group. Rapamycin treatment after LPS and dexamethasone resulted in a significant increase in the IL-10
population and a significant decrease in the IL-1β
population in the NR group.
Dexamethasone treatment resulted in different patterns of change in cytokine expressions in LPS-stimulated CD14++CD16+ p-mTOR monocytes between the R and NR. mTOR inhibition can restore steroid responsiveness involving IL-10 and IL-1β in CD14++CD16+ p-mTOR monocytes.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases; however, it is hard to estimate their incidence due to the rarity of these diseases. We evaluated ...the incidence of SJS and TEN using a nationwide administrative database.
We used a national medical insurance review system (Health Insurance Review and Assessment) database which contained the claim data of the entire nation from 2009 to 2013 to estimate the accurate incidence of SJS and TEN in Korea. The diagnostic codes of L511 (SJS) or L512 (TEN) from the International Classification of Diseases-10th revision were used to define the target study population. We also retrospectively followed up a 2011 SJS and TEN cohort for 24 months in order to assess the in-hospital mortality, related complications and total claims cost due to SJS and TEN.
A total of 1,167 (938 SJS and 229 TEN) cases were newly diagnosed from 2010 to 2013. The age- and sex-standardized annual incidences estimated in this study were 3.96 to 5.03 in SJS and 0.94 to 1.45 in TEN per million. There was no significant change in annual incidence throughout the study periods. When analyzed by 10-year age groups, the annual incidence was the lowest in group 20-29 years and the highest in group 70 for both SJS and TEN. Based on the 2011 cohort analysis, the in-hospital mortality were 5.7 and 15.1% for SJS and TEN, respectively. The mortality increased with age, particularly, after 40 years of age. Among the complications related with SJS or TEN, ocular sequelae was the most common (43.1 and 43.4% of SJS and TEN patients, respectively) followed by urethral sequelae (5.7 and 9.4% of SJS and TEN patients, respectively).
Overall, our data suggest that SJS, and TEN are infrequent but constantly arise throughout the years.
Air pollutant exposure leads to and exacerbates respiratory diseases. Particulate Matter (PM) is a major deleterious factor in the pathophysiology of asthma. Nonetheless, studies on the effects and ...mechanisms of exposure in the early life of mice remain unresolved. This study aimed to investigate changes in allergic phenotypes and effects on allergen-specific memory T cells resulting from co-exposure of mice in the early life to PM and house dust mites (HDM) and to explore the role of interleukin-23 (IL-23) in this process. PM and low-dose HDM were administered intranasally in 4-day-old C57BL/6 mice. After confirming an increase in IL-23 expression in mouse lung tissues, changes in the asthma phenotype and lung effector/memory Th2 or Th17 cells were evaluated after intranasal administration of anti-IL-23 antibody (Ab) during co-exposure to PM and HDM. Evaluation was performed up to 7 weeks after the last administration. Co-exposure to PM and low-dose HDM resulted in increases in airway hyperresponsiveness (AHR), eosinophils, neutrophils, and persistent Th2/Th17 effector/memory cells, which were all inhibited by anti-IL-23 Ab administration. When low-dose HDM was administered twice after a 7-week rest, mice exposed to PM and HDM during the previous early life period exhibited re-increases AHR, eosinophil count, HDM-specific IgG1, and effector/memory Th2 and Th17 cell populations. However, anti-IL-23 Ab administration during the early life period resulted in inhibition. Co-exposure to PM and low-dose HDM reinforced the allergic phenotypes and allergen-specific memory responses in early life of mice. During this process, IL-23 contributes to the enhancement of effector/memory Th2/Th17 cells and allergic phenotypes.
Graphical Abstract
Exposure of Particulate Matter (PM) and a low dose of HDM in mice of early life period induces the expression of IL-23 from CD11c + cells and airway epithelial cells, AHR, eosinophils, neutrophils, effector/memory Th2 and Th17 cells in lung tissue. These changes decreased when anti-IL-23 Ab was administered. When low-dose HDM was administered twice after 7 weeks of rest, mice exposed to PM and HDM during the previous early life period had re-increases in allergic responses, effector/memory Th2, and Th17 cells. The administration of anti-IL-23 Ab in the previous early life period showed their inhibition. HDM, house dust mite; AHR, airway hyperresponsiveness; anti-IL-23 Ab; anti-IL-23 antibody
Key messages
PM-induced IL-23 expression, allergic responses in HDMinstilled mice of early life period.
PM-induced effector/memory Th2/Th17 cells in HDMinstilled mice of early life period.
Inhibition of IL-23 reduced the increase in allergic responses.
Inhibition of IL-23 reduced the increase in allergic responses.
After the resting period, HDM administration showed re-increase in allergic responses.
Inhibition of IL-23 reduced the HDM-recall allergic responses.
Abstract
The role of cellular senescence in the development of asthma is not well known. We aimed to evaluate the susceptibility of mice with cellular senescence to asthma development and determine ...whether the mTOR pathway played an important role in this process. Cellular senescence was induced in mice by intranasal instillation of 2% cigarette smoke extract (CSE). Subsequently, a low dose (0.1 μg) of house dust mite (HDM) allergens, which cause no inflammation and airway hyperresponsiveness (AHR) in mice without cellular senescence, was administered intranasally. To evaluate the role of the mTOR pathway in this model, rapamycin (TORC1 inhibitor) was injected intraperitoneally before CSE instillation. CSE significantly increased senescence-associated β-gal activity in lung homogenate and S100A8/9+ p-mTOR+ population in lung cells. Moreover, S100A8/9+ or HMGB1+ populations in airway epithelial cells with p-mTOR activity increased remarkably. Rapamycin attenuated all changes. Subsequent administration of low-dose HDM allergen induced murine asthma characterized by increased AHR, serum HDM-specific immunoglobulin E, and eosinophilic airway inflammation; these asthma characteristics disappeared after rapamycin injection. In vitro experiments showed significant activation of bone marrow-derived cells cocultured with S100A9 or HMGB1 overexpressing MLE-12 cells treated with HDM allergen, compared to those treated with HDM allergen only. CSE increased the levels of senescence markers (S100A8/9 and HMGB1) in airway epithelial cells, making the mice susceptible to asthma development due to low-dose HDM allergens by activating dendritic cells. Because rapamycin significantly attenuated asthma characteristics, the mTOR pathway may be important in this murine model.
Background
Microbes in the airway have been shown to be associated with the pathogenesis of asthma. The upper airway microbiome influences the dysbiosis of the lower airway microbiome. However, to ...date, the influence of upper airway microbiome for adult and elderly asthma has not been fully elucidated. Here, the metagenome of upper airway microbiome of young adults and elderly was analyzed to identify their association with adult asthma.
Methods
Nasopharyngeal swabs were collected from young adult and elderly asthma patients and non‐asthmatic subjects. The compositions and functional genes of airway microbiome were analyzed by high‐throughput sequencing.
Results
The composition of microbiota differed between young adult and elderly, and it was different between asthmatics and non‐asthmatics in each age group. Different bacteria were related to FEV1% predicted in each age group. Genes related to lysine degradation, N‐glycan biosynthesis, caprolactam degradation, and PPAR signaling pathway, which could be related to the reduction in inflammation and degradation of air pollutants, were higher in non‐asthmatics. Genes related to pentose phosphate pathway, lipopolysaccharide biosynthesis, flagella assembly, and bacterial chemotaxis—which may all be related to increased inflammation and colonization of pathogenic bacteria—were higher in young adult asthmatic patients. However, the functional genes of airway microbiome in elderly patients were not significantly different according to asthma morbidity.
Conclusions
These results suggest that the composition and function of upper airway microbiome could influence asthma pathogenesis, and the microbiome could play various roles depending on the age group.
The upper airway microbiome was different between young adults and elderly, and their association with asthma was also different.
The microbiome genes reducing airway inflammation and degrading air pollutants were lower in asthmatics, whereas genes enhancing inflammation and mucosal bacterial colonization were higher in asthmatics of young adults.
The composition and function of upper airway microbiome could influence asthma pathogenesis, and the microbiome could play various roles depending on the age group.
Although it has been reported that cellular senescence is important in the pathogenesis of asthma, the differential effects of diesel exhaust particle (DEP)-induced cellular senescence on the ...development of asthma according to age have not been thoroughly studied.
We first confirmed that DEP induced cellular senescence in mouse lungs, and then that DEP-induced cellular senescence followed by intranasal instillation of a low-dose house dust mite (HDM) allergen resulted in murine asthma. Second, we examined age-dependent differential effects using 6-week-old (young) and 18-month-old mice (old), and tested whether the mammalian target of the rapamycin (mTOR) pathway plays an important role in this process. Finally, we performed in vitro experiments using human bronchial epithelial cells (HBEC) originating from young and elderly adults to identify the underlying mechanisms.
DEP induced cellular senescence in the airway epithelial cells of young and old mice characterized by increased senescence-associated beta-galactosidase, S100A8/9, and high mobility group box 1 (HMGB1) expressions. DEP-induced cellular senescence with subsequent exposure to a low-dose HDM allergen resulted in asthma in young and old mice. Rapamycin (mTOR pathway inhibitor) administration before DEP instillation significantly attenuated these asthmatic features. In addition, after treatment with a low-dose HDM allergen, S100A9 and HMGB1 over-expressed HBEC originating from young and elderly adults greatly activated co-cultured monocyte-derived dendritic cells (DCs).
This study showed that DEP-induced senescence made both young and old mice susceptible to allergic sensitization and resultant asthma development by enhancing DC activation. Public health efforts to reduce DEP exposure are warranted.
Display omitted
There is very limited evidence regarding long-term prognosis of chronic cough. We examined longitudinal outcomes among patients with chronic cough, and explored predictors of cough persistence.
A ...retrospective cohort was constructed of adults who had newly visited a specialist cough clinic in 2012–2013. All had undergone systematic investigation for chronic cough. The Hull Airway Reflux Questionnaire (HARQ) was administered to assess reflux cough symptoms. A follow-up survey was conducted in 2016–2017 to assess cough persistence.
From 418 candidates, 323 participated in the follow-up study; main analyses focused on patients with chronic persistent cough (n = 64; 19.8%) and remitted cough (n = 193; 59.8%). Compared with remitted cough group, chronic persistent cough group had more family history of chronic cough (17.2% vs. 4.7%, p = 0.001) and cold air-sensitive cough (62.5% vs. 44.6%, p = 0.013). The total HARQ score did not differ; however, two items (cough with eating and cough with certain foods) scored significantly higher in chronic persistent cough. In multivariate analyses, a family history of chronic cough (adjusted odds ratio 4.27 95% confidence interval 1.35–9.89), cold air-sensitive cough (2.01 1.09–3.73), and cough with eating (1.22 1.02–1.45) were associated with chronic persistent cough at 4 years.
Cough persists in about 20% of patients after 4 years following systematic assessment and treatments. Several cough characteristics, such as family history, cold air-sensitivity, or reflux cough, may be associated with cough persistence. Larger cohort studies are warranted to further understand long-term prognosis and confirm predictors of persistence in patients with chronic cough.
Display omitted
1.8-Cineole (eucalyptol) is a phytoncide, a volatile organic compound derived from plants. Phytoncides are known to have an anti-inflammatory effect. However, the effects of 1.8-cineole in house dust ...mite (HDM)-stimulated bronchial epithelial cells are poorly understood. The objective of this study was to assess the effect of 1.8-cineole in HDM-stimulated bronchial epithelial cells and in the HDM-induced murine asthma model. The purpose of the present study is to evaluate the anti-inflammatory effects and mechanism of 1.8-cineole action in HDM-induced airway inflammation. Human bronchial epithelial cells (HBECs) were cultured with Dermatophagoides pteronyssinus (Der p) and 1.8-cineole. Cytokine protein levels, phosphorylation of protein kinases, and intracellular Toll-like receptor 4 (TLR4) expressions were measured. In the murine model, BALB/C mice were sensitized with Der p and were exposed to Der p via intranasal route during the challenge period. 1.8-Cineole was given by inhalation 6 h before the each challenge. Treatment with 1.8-cineole inhibited the Der p-induced cytokine protein expression, phosphorylation of p38 mitogen-activated protein kinase (MAPK) and Akt and intracellular TLR4 expression in HBECs. In the Der p-induced mouse model, airway hyper-responsiveness (AHR) and the number of eosinophils in bronchoalveolar lavage fluid (BALF) was also significantly reduced by 1.8-cineole treatment. The treatment of 1.8-cineole inhibited the increased production of interleukin (IL)-4, IL-13 and IL-17A in BALF after Der p challenge. These results suggest that 1.8-cineole suppresses Der p-induced IL-8, IL-6 and granulocyte macrophage-colony stimulating factor (GM-CSF) production in HBECs. Finally, we confirmed that 1.8-cineole decreases AHR and eosinophilic airway inflammation in Der p-induced asthma mice.
PDF
