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Abstract Allergic asthma is a chronic inflammatory disease of the airways. T lymphocytes play an important role in the pathogenesis of asthma. The voltage-gated Kv1.3 potassium channel is a target for the preferential inhibition of T EM cells. In this study, we investigate the effects of PAP-1, a selective inhibitor of Kv1.3 channel, on the treatment of the neutrophilic asthma model. PAP-1 (40 mg/kg) was injected intraperitoneally into ovalbumin (OVA)-lipopolysaccharide (LPS)-challenged BALB/c mice. We found that the expression of the Kv1.3 channel in the lung tissues, and the intensity of the Kv current in the asthmatic mice increased clearly compared with those in normal control. PAP-1 significantly reduced airway hyperresponsiveness (AHR), inflammatory cell count in the bronchoalveolar lavage fluids (BALF) and serum, and attenuated airway inflammation in a histological examination of the asthmatic mice. Moreover, PAP-1 inhibited the OVA-LPS-induced imbalance of Th1/Th2, Treg/Th17 lymphocytes, and reduced levels of IL-4 and IL-17, inducing an increase in the production of IFN-γ and IL-10. Furthermore, the activation of the extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) pathway in the lungs of the asthmatic mice was suppressed by PAP-1. We also found that PD-98059, an inhibitor of ERK, had a similar effect with PAP-1 in terms of regulating the imbalance of Th1/Th2, Treg/Th17 cytokines. However, PD-98059 could not further influence cytokine changes when the cells were treated with PAP-1. The results suggest that ERK acts as a downstream regulator of inhibitors of the Kv1.3 channel in neutrophilic asthma. In conclusion, the inhibitor of the Kv1.3 channel has therapeutic potential for treating asthma. Highlights • Expression and activities of Kv1.3 channel in lung tissue in asthmatic mice • PAP-1 significantly reduced the airway hyperresponsiveness and airway, inflammation in asthmatic mice. • PAP-1 inhibited OVA-LPS induced imbalance of Th1/Th2,Treg/Th17 lymphocytes. • The mechanism may relate to the inhibiting the ERK-NF-κB signaling pathway [ABSTRACT FROM AUTHOR]

Abstract Background Epidemiologic evidence indicates common risk factors, including air pollution exposure, for respiratory and cardiovascular diseases, suggesting the involvement of common altered molecular pathways. Objectives The goal was to find intermediate metabolites or metabolic pathways that could be associated with both air pollutants and health outcomes (“meeting-in-the-middle”), thus shedding light on mechanisms and reinforcing causality. Methods We applied a statistical approach named ‘meet-in-the-middle’ to untargeted metabolomics in two independent case-control studies nested in cohorts on adult-onset asthma (AOA) and cardio-cerebrovascular diseases (CCVD). We compared the results to identify both common and disease-specific altered metabolic pathways. Results A novel finding was a strong association of AOA with ultrafine particles (UFP; odds ratio 1.80 [1.26, 2.55] per increase by 5000 particles/cm3). Further, we have identified several metabolic pathways that potentially mediate the effect of air pollution on health outcomes. Among those, perturbation of Linoleate metabolism pathway was associated with air pollution exposure, AOA and CCVD. Conclusions Our results suggest common pathway perturbations may occur as a consequence of chronic exposure to air pollution leading to increased risk for both AOA and CCVD. Highlights • Strong association of long-term ultrafine particle exposure with adult-onset asthma • Linoleate metabolism and carnitine shuttle as “meeting-in-the-middle” pathways. • Metabolic pathways mediate the air pollution effects on health outcomes. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to assess whether smoking status among individuals in late adolescence (19-22 years) with asthma was associated with socioeconomic status (SES) defined by HOUSES, an individual-housing-based SES measure.Methods: A population-based cross-sectional study was conducted among the 1988-1989 Olmsted County, Minnesota Birth Cohort, with physician-diagnosed asthma and that lived in the community during the study period (November 1, 2008-October 31, 2012). Using a z score for housing value, actual square footage, and numbers of bedrooms and bathrooms, HOUSES was formulated and categorized into quartiles. Smoking status (both current and past smoker) was compared among subjects with different SES as measured by HOUSES using logistic regression, adjusting for age and sex.Results: Among 289 eligible subjects, 287 (99%) were successfully geo-coded to real property data for HOUSES. Of the 257 subjects whose smoke exposure was recorded, 70 (27%) had a history of smoking (either past or current). An inverse association was observed between HOUSES and smoking status after accounting for age, gender, and General Medical Examination status (adjusted OR = 0.39, 95% CI = 0.18-0.87 for comparing highest vs. lowest HOUSES in quartile; overall P = .02).Conclusions: A significant proportion of individuals with asthma in late adolescence was smokers during the study period, disproportionally affecting those with lower SES. [ABSTRACT FROM AUTHOR]

Cat allergy is one of the most prevalent allergies worldwide and can lead to the development of rhinitis and asthma. Thus far, only allergen extracts from natural sources have been used for allergen-specific immunotherapy. However, extracts and whole allergens in immunotherapy present an anaphylaxis risk. Identification of allergen epitopes or mimotopes has an important role in development of safe and effective allergen-specific immunotherapy. Moreover, with a suitable immunogenic carrier, the absence of sufficient immune response elicited by short peptides could be surmounted. In this study, we identified five structural mimotopes of the major cat allergen Fel d 1 by immunoscreening with random peptide phage libraries. The mimotopes were computationally mapped to the allergen surface, and their IgE reactivity was confirmed using sera from cat-allergic patients. Importantly, the mimotopes showed no basophil activation of the corresponding cat-allergic patients, which makes them good candidates for the development of hypoallergenic vaccine. As bacteriophage particles are becoming increasingly recognized as immunogenic carriers, we constructed bacteriophage particles displaying multiple copies of each selected mimotope on major phage coat protein. These constructed phages elicited T cell-mediated immune response, which was predominated by the type 1 T cell response. Mimotopes alone contributed to the type 1 T cell response by promoting IL-2 production. Fel d 1 mimotopes, as well as their filamentous phage immunogenic carriers, represent promising candidates in the development of hypoallergenic vaccine against cat allergy. [ABSTRACT FROM AUTHOR]

Airway narrowing by smooth muscle constriction is a hallmark of asthma attacks that may cause severe difficulties of breathing. However, the causes of asthma and the underlying mechanisms are not fully understood. Bronchoconstriction within a bronchial tree involves complex interactions among the airways that lead to the emergence of regions of poor ventilation (ventilation defects, VDefs) in the lungs. The emphasis of this review is on mathematical modeling of the mechanisms involved in bronchoconstriction and the emergence of the complex airway behavior that leads to VDefs. Additionally, the review discusses characteristic model behaviors and experimental data to demonstrate advances and limitations of different models. [ABSTRACT FROM AUTHOR]

Abstract: It has been suggested that mitochondrial dysfunction plays a role in the pathogenesis of asthma. To test whether mitochondrial variants influence the risk of asthma, we analyzed 16,158 mtSNPs in a sample of 372 asthmatic children and 395 healthy children using the DNA pooling technique and genome wide association analysis. Stratified analysis by sex was performed to explain the differences observed between sexes in the etiology of asthma. Different variants were detected to be significant in the sample of girls and boys with the smallest adjusted p values being 1.4×10−09 (mt5295) and 3.6×10−12 (mt16158), respectively. Most of the significant locations found in boys are within the CYB gene and the non-coding region. For girls, most of the significant mtSNPs lie within NADH-dehydrogenase-subunits. The variants reported here have not previously been described in connection with asthma. Although further studies in other cohorts are needed to confirm these findings our study highlights the importance of the mitochondria among the factors that contribute to the risk of asthma. [Copyright &y& Elsevier]

Abstract: Methylene diphenyl diisocyanate (MDI), a low molecular weight chemical important for producing polyurethane foam, coatings, and elastomers is a major cause of occupational asthma, however, mechanisms of disease pathogenesis remain poorly understood. This study characterizes the rearranged germline and hypervariable region cDNA of new anti-MDI secreting hybridomas derived from mice immunized with MDI-conjugated to autologous serum proteins. Six IgG1 secreting clones were identified in initial screening ELISAs, based on differential binding to MDI conjugated human albumin vs. mock exposed albumin. The mAbs secreted by the hybridomas also recognized MDI conjugated to other model proteins (e.g. ovalbumin, transferrin), but did not bind unconjugated proteins, or protein conjugates prepared with other isocyanates (e.g. TDI, HDI). The mAbs displayed MDI-dose dependent binding in ELISA and Western blot, and exhibited varying degrees of cross-competition, suggesting differences in epitope specificity. The cDNA encoding the monoclonal antibodies reveal clonal differences in the CDR3 regions, germline gene usage, and patterns of somatic hypermutation related to epitope specificity. Together, the data provide new insight into the molecular determinants of humoral MDI specificity, and characterize anti-MDI IgG1 mAbs that may be developed into useful diagnostic reagents. [Copyright &y& Elsevier]

Abstract: A daily moisturizing routine is a vital part of the management of patients with atopic dermatitis and other dry skin conditions. The composition of the moisturizer determines whether the treatment strengthens or deteriorates the skin barrier function, which may have consequences for the outcome of the dermatitis. One might expect that a patient''s impaired skin barrier function should improve in association with a reduction in the clinical signs of dryness. Despite visible relief of the dryness symptoms, however, the abnormal transepidermal water loss has been reported to remain high, or even to increase under certain regimens, whereas other moisturizers improve skin barrier function. Differing outcomes have also been reported in healthy skin: some moisturizers produce deterioration in skin barrier function and others improve the skin. Possible targets for barrier-influencing moisturizing creams include the intercellular lipid bilayers, where the fraction of lipids forming a fluid phase might be changed due to compositional or organizational changes. Other targets are the projected size of the corneocytes or the thickness of the stratum corneum. Moisturizers with barrier-improving properties may delay relapse of dermatitis in patients with atopic dermatitis. In a worst-case scenario, treatment with moisturizing creams could increase the risks of dermatitis and asthma. [Copyright &y& Elsevier]

Background: Allergic asthma is characterized by reversible airway obstruction and bronchial hyperresponsiveness associated with TH2 cell–mediated inflammation. Cysteinyl leukotrienes (CysLTs) are potent lipid mediators involved in bronchoconstriction, mucus secretion, and cell trafficking in asthmatic patients. Recent data have implicated CysLTs in the establishment and amplification of TH2 responses in murine models, although the precise mechanisms are unresolved. Objectives: Preliminary microarray studies suggested that human TH2 cells might selectively express cysteinyl leukotriene receptor 1 (CYSLTR1) mRNA. We sought to establish whether human TH2 cells are indeed a CysLT target cell type. Methods: We examined the expression of CYSLTR1 using real-time PCR in human TH1 and TH2 cells. We functionally assessed cysteinyl leukotriene receptor 1 protein (CysLT1) expression using calcium flux, cyclic AMP, and chemotaxis assays. Results: We show that human TH2 cells selectively express CYSLTR1 mRNA at high levels compared with TH1 cells after in vitro differentiation from naive precursors. Human TH2 cells are selectively responsive to CysLTs in a calcium flux assay when compared with TH1 cells with a rank order of potency similar to that described for CysLT1 (leukotriene [LT] D4 > LTC4 > LTE4). We also show that LTD4-induced signaling in TH2 cells is mediated through CysLT1 coupled to Gαq and Gαi proteins, and both pathways can be completely inhibited by selective CysLT1 antagonists. LTD4 is also found to possess potent chemotactic activity for TH2 cells at low nanomolar concentrations. Conclusions: These findings suggest a novel mechanism of action for CysLTs in the pathogenesis of asthma and provide a potential explanation for the anti-inflammatory effects of CysLT1 antagonists. [ABSTRACT FROM AUTHOR]

Background: Asthma morbidity and mortality rates are high among young inner-city children. Lack of routine primary care provider visits, poor access to care, and poor patient-physician communication might be contributing factors. Objective: This study evaluated the effects of providing Breathmobile services only, a Facilitated Asthma Communication Intervention (FACI) only, or both Breathmobile plus FACI on asthma outcomes relative to standard care. Methods: Children with asthma (n = 322; mean age, 4 years; 53% male; 97% African American) were recruited from Head Start programs in Baltimore City and randomized into 4 groups. Outcome measures included symptom-free days (SFDs), urgent care use (emergency department visits and hospitalizations), and medication use (courses of oral steroids and proportion taking an asthma controller medication), as reported by caregivers at baseline, 6-month, and 12-month assessments. Generalized estimating equations models were conducted to examine the differential treatment effects of the Breathmobile and FACI compared with standard care. Results: Children in the combined treatment group (Breathmobile plus FACI) had an increase of 1.7 (6.6%) SFDs that was not maintained at 12 months. In intent-to-treat analyses the FACI-only group had an increase in the number of emergency department visits at 6 months, which was not present at 12 months or in the post hoc as-treated analyses. No significant differences were found between the intervention groups compared with those receiving standard care on all other outcome measures. Conclusions: Other than a slight improvement in SFDs at 6 months in the Breathmobile plus FACI group, the intervention components did not result in any significant improvements in asthma management or asthma morbidity. [ABSTRACT FROM AUTHOR]

Background: Laryngopharyngeal reflux (LPR) can cause atypical symptoms, asthma, and pulmonary fibrosis. The aim of this study was to establish the normative data for LPR using hypopharyngeal multichannel intraluminal impedance-pH (HMII). Methods: Asymptomatic subjects underwent endoscopy followed by 24-h HMII using a specialized impedance catheter configured to detect LPR before and after a 2-week course of proton pump inhibitors (PPI). Subjects were excluded if they had esophageal pathology or a positive DeMeester score. A cohort of 24 LPR patients who had a complete response to treatment was used for comparison with the normative data. Results: Forty subjects were enrolled. Thirty-four subjects completed one, and 25 completed both HMII testing periods off and on PPI. There was no difference in the total number of reflux events between off and on PPI [22 (8-32) and 24 (10-28), respectively, p = 0.89]. The 95th percentiles of LPR off and on PPI were 0 and 1, respectively. All patients with treatment responsive LPR had pre-treatment HMII values of LPR greater than the 95th percentile. Conclusion: LPR events are rare in an asymptomatic population. One or more LPR events should be considered abnormal in patients with LPR symptoms regardless of whether there is a positive DeMeester score. [ABSTRACT FROM AUTHOR]

Abstract: Bronchial asthma is a chronic disorder characterized by airway inflammation, reversible airway obstruction, and airway hyperresponsiveness. Eosinophils are believed to play important roles in the pathogenesis of asthma through the release of inflammatory mediators. In refractory eosinophilic asthma, anti-IL-5 mAb reduces exacerbations and steroid dose, indicating roles of eosinophils and IL-5 in the development of severe eosinophilic asthma. Even in the absence of IL-5, it is likely that the “Th2 network”, including a cascade of vascular cell adhesion molecule-1/CC chemokines/GM-CSF, can sufficiently maintain eosinophilic infiltration and degranulation. Cysteinyl leukotrienes can also directly provoke eosinophilic infiltration and activation in the airways of asthma. Therefore, various mechanisms would be involved in the eosinophilic airway inflammation of asthma. In the pathogenesis of severe asthma, not only eosinophils but also mast cells or neutrophils play important roles. Mast cells are much infiltrated to smooth muscle in severe asthma and induce airway remodeling by release of inflammatory mediators such as amphiregulin. Treatment with anti-IgE Ab, which neutralizes circulating IgE and suppresses mast cell functions, reduces asthma exacerbations in severe asthmatic patients. Furthermore, infiltration of neutrophils in the airway is also increased in severe asthma. IL-8 plays an important role in the accumulation of neutrophils and is indeed upregulated in severe asthma. In the absence of chemoattractant for eosinophils, neutrophils stimulated by IL-8 augment the trans-basement membrane migration of eosinophils, suggesting that IL-8-stimulated neutrophils could lead eosinophils to accumulate in the airways of asthma. In view of these mechanisms, an effective strategy for controlling asthma, especially severe asthma, should be considered. [Copyright &y& Elsevier]

2010 found a number of significant advances in environmental and occupational respiratory disease. The role of sensitization and the subsequent production of allergic disease have been explored. New allergens and their T- and B-cell epitopes have been characterized. Novel approaches to the diagnosis and evaluation of food allergy have been described. The role of pollutants as they affect respiratory disease and the effects of age extremes on sensitization and asthma have been addressed. Significant advances in the understanding of inflammatory changes in both the upper and lower respiratory systems occurred. Novel therapeutic approaches have been explored, including the development of hypoallergens from improved molecular biology techniques. New effective approaches to asthma therapy have been identified. Exposure reduction through air filtration and novel immunotherapy approaches, such as sublingual therapy, have made significant advances. [ABSTRACT FROM AUTHOR]

Abstract: It has been suggested that one possible contributor to the increasing prevalence of atopic (IgE-mediated) allergic diseases and asthma in Europe and the US is exposure to chemicals that may act as adjuvants. Certain commonly used phthalate plasticisers, such as di-(2-ethylhexyl) phthalate, have been implicated in this regard. The evidence for the ability of phthalates to impact on immune and allergic responses has been examined, encompassing epidemiological investigations and results deriving from studies using experimental animals and from analyses in vitro. The epidemiological data provide some evidence that exposure to phthalates may be associated with increased risk of development of allergies and asthma, however, the lack of objective exposure information limits the interpretation. A variety of studies have been performed in mice to examine the influence of phthalate (delivered via various routes of exposure) to impact on immune responses. Measurement of antibody responses is the commonest read out, although other parameters of inflammation such as eosinophil infiltration and cytokine production have been used also. Although certain phthalates, when delivered at appropriate doses, and via an appropriate route, have been reported to impact on immune and inflammatory function in rodents, as yet no consistent pattern has emerged. Results ranged from potentiation of immune or inflammatory responses, to the absence of any effect, to inhibitory or immunosuppressive activity. In addition, comparatively low doses of phthalates have been associated with immune effects only when routes of administration (subcutaneous or intraperitoneal) are used that do not reflect, and are much less relevant for, opportunities for human contact with phthalates. There is clearly a case to be made for the design of more definitive animal studies that will allow development of a more detailed understanding of whether and to what extent, and under what conditions, phthalates are able to effect meaningful changes in immune function that may in turn impact on human health. [Copyright &y& Elsevier]

Background: Epidemiologic findings support a positive association between asthma and obesity. Objective: Determine whether obesity or increasing level of body mass index (BMI) are associated with worse asthma control in an ethnically diverse urban population. Methods: Cross-sectional assessment of asthma control was performed in patients with asthma recruited from primary care offices by using 4 different validated asthma control questionnaires: the Asthma Control and Communication Instrument (ACCI), the Asthma Control Test (ACT), the Asthma Control Questionnaire (ACQ), and the Asthma Therapy Assessment Questionnaire (ATAQ). Multiple linear regression analysis was performed to evaluate the association between obesity and increasing BMI level and asthma control. Results: Of 292 subjects with a mean age of 47 years, the majority were women (82%) and African American (67%). There was a high prevalence of obesity with 63%, with only 15% normal weight. The mean score from all 4 questionnaires showed an average suboptimal asthma control (mean score/maximum possible score): ACCI (8.3/19), ACT (15.4/ 25), ACQ (2.1/ 6), and ATAQ (1.3/ 4). Regression analysis showed no association between obesity or increasing BMI level and asthma control using all 4 questionnaires. This finding persisted even after adjusting for FEV1, smoking status, race, sex, selected comorbid illnesses, and long-term asthma controller use. Conclusion: Using 4 validated asthma control questionnaires, we failed to find an association between obesity and asthma control in an urban population with asthma. Weight loss may not be an appropriate strategy to improve asthma control in this population. [Copyright &y& Elsevier]

Background: Asthma-associated morbidity is rising, especially in inner city children. Objective: We evaluated the allergen sensitivities, allergen exposures, and associated morbidity for participants in the Inner City Asthma Study. We also determined geographic variations of indoor allergen levels. Methods: Nine hundred thirty-seven inner city children 5 to 11 years old with moderate to severe asthma underwent allergen skin testing. Bedroom dust samples were evaluated for Der p 1, Der f 1, Bla g 1, Fel d 1, and Can f 1. Results: Skin test sensitivities to cockroach (69%), dust mites (62%), and molds (50%) predominated, with marked study site–specific differences. Cockroach sensitivity was highest in the Bronx, New York, and Dallas (81.2%, 78.7%, and 78.5%, respectively), and dust mite sensitivity was highest in Dallas and Seattle (83.7% and 78.0%, respectively). A majority of homes in Chicago, New York, and the Bronx had cockroach allergen levels greater than 2 U/g, and a majority of those in Dallas and Seattle had dust mite allergen levels greater than 2 μg/g. Levels of both of these allergens were influenced by housing type. Cockroach allergen levels were highest in high-rise apartments, whereas dust mite allergen levels were highest in detached homes. Children who were both sensitive and exposed to cockroach allergen had significantly more asthma symptom days, more caretaker interrupted sleep, and more school days missed than children who were not sensitive or exposed. Conclusion: Geographic differences in allergen exposure and sensitivity exist among inner city children. Cockroach exposure and sensitivity predominate in the Northeast, whereas dust mite exposure and sensitivity are highest in the South and Northwest. Cockroach allergen appears to have a greater effect on asthma morbidity than dust mite or pet allergen in these children. [ABSTRACT FROM AUTHOR]

Background: The specific cause or causes of asthma development must be identified to prevent this disease. Objective: Our hypothesis was that specific mold exposures are associated with childhood asthma development. Methods: Infants were identified from birth certificates. Dust samples were collected from 289 homes when the infants were 8 months of age. Samples were analyzed for concentrations of 36 molds that comprise the Environmental Relative Moldiness Index (ERMI) and endotoxin, house dust mite, cat, dog, and cockroach allergens. Children were evaluated at age 7 years for asthma based on reported symptoms and objective measures of lung function. Host, environmental exposure, and home characteristics evaluated included a history of parental asthma, race, sex, upper and lower respiratory tract symptoms, season of birth, family income, cigarette smoke exposure, air conditioning, use of a dehumidifier, presence of carpeting, age of home, and visible mold at age 1 year and child''s positive skin prick test response to aeroallergens and molds at age 7 years. Results: Asthma was diagnosed in 24% of the children at age 7 years. A statistically significant increase in asthma risk at age 7 years was associated with high ERMI values in the child''s home in infancy (adjusted relative risk for a 10-unit increase in ERMI value, 1.8; 95% CI, 1.5-2.2). The summation of levels of 3 mold species, Aspergillus ochraceus, Aspergillus unguis, and Penicillium variabile, was significantly associated with asthma (adjusted relative risk, 2.2; 95% CI, 1.8-2.7). Conclusion: In this birth cohort study exposure during infancy to 3 mold species common to water-damaged buildings was associated with childhood asthma at age 7 years. [Copyright &y& Elsevier]

Background: Asthma typically originates in early-life, and the impact of infection during immunologic maturation is a critical factor in disease pathogenesis. The progression of aberrant TH2 cell responses and disease development has been attributed to a lack of infections. However, exposure to specific pathogens such as Chlamydia may alter immunologic programming and predispose to asthma. Objective: To investigate the effects of chlamydial infection at different ages on allergic airways disease in later life. Methods: Neonatal, infant, or adult BALB/c mice were infected and 6 weeks later were sensitized and subsequently challenged with ovalbumin. Hallmark features of allergic airways disease were compared with uninfected allergic and nonallergic controls. Results: Early-life (neonatal and infant) but not adult chlamydial infection enhanced the development of hallmark features of asthma in ovalbumin-induced allergic airways disease. Notably early-life infection increased mucus-secreting cell numbers, IL-13 expression, and airway hyperresponsiveness. Neonatal infection attenuated eosinophil influx and ovalbumin-specific TH2 cytokine release and numbers of activated myeloid dendritic cells (DCs) in lymph nodes. By contrast, infant infection augmented features of allergic inflammation with increased airway eosinophils, TH2 cytokine, and DC responses. Both neonatal and infant infection increased systemic DC-induced IL-13 release from CD4+ T cells. The timing of infection had significant effects on lung structure because neonatal but not infant or adult infection induced increases in alveolar diameter. Conclusion: Early-life respiratory chlamydial infections modulate immune responses, alter lung function and structure, and enhance the severity of allergic airways disease in later life. [Copyright &y& Elsevier]