A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13).

BACKGROUND: Rhinovirus infection is a major cause of asthma exacerbations. OBJECTIVES: We studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations. METHODS: We used nasosorption on days 0, 2-5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n=28) and healthy non-atopic controls (n=11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay. RESULTS: Following rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P<0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-γ, IFN-λ/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0-7, all P<0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P<0.01) and levels increased by days 3 and 4 (P<0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-γ, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P<0.05). CONCLUSIONS: Precision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation

"Ingen lag eller förordning är mäktigare än förståelsen"

Ökat valutbud och komplexa valsituationer gör att ungdomar behöver utveckla valkompetens för att ha beredskap att möta ett framtida yrkesliv och en arbetsmarknad i ständig förändring. En kompetens vilken kräver färdigheter som skapas genom process över tid och innefattar förmågan att utifrån självkännedom samt vetskap om utbud kunna fatta och genomföra beslut och som är ett studie- och yrkesvägledande uppdrag som vilar på hela skolans ansvar, men där flertalet granskningar visat på brister i kontinuitet och kvalité. Studiens syfte varit att analysera mellanstadielärares förutsättningar för arbete med studie- och yrkesvägledning i undervisningen. Sex lärare har intervjuats för att undersöka hur deras förståelse, kunnande och vilja ser ut, i förhållande till uppdraget. Ett av studiens tydligaste resultat visar, i likhet med tidigare forskning, på bristande medvetenhet om ansvar och innebörden av uppdraget. Lärare likställer studie- och yrkesvägledning främst med den informativa delen inför gymnasiet, så som behörighetskrav, regelverk samt programutbud och ser studie- och yrkesvägledaren som ansvarig. Denna förståelse kan antas vara en förklaring till utebliven förändring trots påvisade brister över tid, då förståelse, kunnande och vilja i växelverkan är betydande förutsättningar för förändring i enlighet med implementeringsteori

Oxidative Stress-induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease

Rationale: There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on “self” proteins. Objectives: To determine the presence of autoantibodies to carbonyl-modified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins. Methods: Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 weeks. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochemistry, and cellular activation by ELISA and fluorescence-activated cell sorter. Measurements and Main Results: Antibody titer against carbonyl-modified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also observed. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonyl-modified protein. Conclusions: Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody production, providing a link by which oxidative stress could drive an autoimmune response in COPD

Inhibitors of proteases and p38 MAPK differentially inhibit apical and basolateral IL-8 release after <i>Alternaria</i> challenge.

<p>The effect of <i>Alternaria</i> extract (100 μg/ml) on 16HBE cells was tested alone or in the presence of AEBSF (250 μM), E-64 (50 μM), Pepstatin A (0.5 μg/ml) or SB203580 (25 μM) (n = 3–8). IL-8 release 24 h post-challenge was calculated as “Release (% control)  =  ((Alt_INHIB – No Alt_INHIB)/(Alt_NO_INHIB – No Alt_{NO INHIB})) ×100”, to correct for any effect of the inhibitors on baseline IL-8 release without <i>Alternaria</i>. Data show mean ± SEM. Analysis as for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071278#pone-0071278-g001" target="_blank">Figure 1</a>; * p<0.05, ** p<0.01.</p

<i>Alternaria</i> extract induces a heat-labile increase in IL-8 release and rapid reduction in TER in polarised 16HBE cells.

<p>Polarised 16HBE cells on Transwell inserts were challenged apically with varying doses of <i>Alternaria</i> (Alt) or <i>Cladosporium</i> (Clad) fungal extracts, or heat treated fungal extract. (A) Apical and (B) basolateral supernatants were harvested 24 h post-challenge. IL-8 concentration was determined by ELISA (n = 4–9). TER was measured before challenge and at (C) 1h and (D) 24 h thereafter, and calculated as percentage change from pre-challenge readings (n = 4–15). Bars represent mean ± SEM. Analysis by one way repeated measures ANOVA with Bonferroni correction for pairwise analyses *** p<0.001.</p

ALI cultures of healthy, but not severely asthmatic, donors increase IL-8 release in response to <i>Alternaria</i>.

<p>ALI cultures from healthy (n = 8–12) or severely asthmatic (n = 6–7) donors were differentiated at air-liquid interface, prior to challenge with <i>Alternaria</i> (Alt) or <i>Cladosporium</i> (Clad) fungal extracts. IL-8 release 24 h post-challenge was determined by ELISA. Box shows median and 25^th/75^th percentiles, and whiskers show 10^th/90^th percentiles. Analysis by Friedman's test with Tukey's correction for pairwise analyses; * p<0.05.</p

Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation

Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2–driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro–type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation