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Rationale: The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. Objectives: To conduct a screening of circulating proteins in childhood asthma and to study proteins that emerged from human studies in a mouse model of asthma. Methods: We included 2,264 children from eight birth cohorts from the Mechanisms of the Development of ALLergy project and the Tucson Children's Respiratory Study. In cross-sectional analyses, we tested 46 circulating proteins for association with asthma in the selection stage and carried significant signals forward to a validation and replication stage. As CK (creatine kinase) was the only protein consistently associated with asthma, we also compared whole blood CK gene expression between subjects with and without asthma ( n  = 249) and used a house dust mite (HDM)-challenged mouse model to gain insights into CK lung expression and its role in the resolution of asthma phenotypes. Measurements and Main Results: As compared with the lowest CK tertile, children in the highest tertile had significantly lower odds for asthma in selection (adjusted odds ratio, 95% confidence interval: 0.31; 0.15-0.65; P  = 0.002), validation (0.63; 0.42-0.95; P  = 0.03), and replication (0.40; 0.16-0.97; P  = 0.04) stages. Both cytosolic CK forms ( CKM and CKB ) were underexpressed in blood from asthmatics compared with control subjects ( P  = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. Conclusions: Circulating concentrations and gene expression of CK are inversely associated with childhood asthma. Mouse models support a possible direct involvement of CK in asthma protection via inhibition of airway hyperresponsiveness and reduction of airway mucin.

Titanium dioxide nanoparticles (TiO 2 NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO 2 NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO 2 NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO 2 NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO 2 NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO 2 NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO 2 NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO 2 NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO 2 NP-mediated respiratory toxicity.

Background: Healthcare workers are at risk for occupational chronic hand eczema (CHE) because of frequent handwashing and prolonged use of occlusive gloves. Prevention programs based on skin care education have been shown to be beneficial. We developed and assessed the efficacy of a skin care educational intervention for healthcare workers of our hospital., Methods: The intervention consisted of two sessions, one week apart, each divided in a theoretical and a practical part, focusing on the skin barrier, types of eczema, risk factors for CHE, hand hygiene measures respectful of the skin, proper use of protective gloves and emollient creams. Its efficacy was assessed by a questionnaire, administered before and after the intervention, investigating the participants' knowledge of risk factors for CHE and risk behaviors., Results: Twenty-three subjects, mostly (65.2%) nurses, took part in the intervention; 60.9% had a self-reported atopic background and 65.2% participants reported a history of CHE. The intervention improved significantly the participants' knowledge on CHE risk factors, i.e. frequent handwashing (P=0.023), surgical scrubbing (P=0.016) and prolonged glove wearing (P=0.022). The frequency of hand washing was significantly reduced (P=0.022). The participants gave a positive unanimous feedback., Conclusions: Our intervention was effective, by significantly improving the participants' knowledge and by inducing significant behavioral changes. Improving the formulation of alcoholic hand rubs may be a key factor to encourage their use. Coexisting nonoccupational risk behaviors are just as important in the prevention of CHE.

In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from n -hexane extract from leaves of Nectandra leucantha and chemically prepared using oxidative coupling from eugenol, was evaluated in an experimental model of mixed-granulocytic asthma. Initially, in silico studies of biseugenol showed good predictions for drug-likeness, with adherence to Lipinski's rules of five (RO5), good Absorption, Distribution, Metabolism and Excretion (ADME) properties and no alerts for Pan-Assay Interference Compounds (PAINS), indicating adequate adherence to perform in vivo assays. Biseugenol (20 mg·kg -1 ) was thus administered intraperitoneally (four days of treatment) and resulted in a significant reduction in both eosinophils and neutrophils of bronchoalveolar lavage fluid in ovalbumin-sensitized mice with no statistical difference from dexamethasone (5 mg·kg -1 ). As for lung function parameters, biseugenol (20 mg·kg -1 ) significantly reduced airway and tissue damping in comparison to ovalbumin group, with similar efficacy to positive control dexamethasone. Airway hyperresponsiveness to intravenous methacholine was reduced with biseugenol but was inferior to dexamethasone in higher doses. In conclusion, biseugenol displayed antiasthmatic effects, as observed through the reduction of inflammation and airway hyperresponsiveness, with similar effects to dexamethasone, on mixed-granulocytic ovalbumin-sensitized mice.

Introduction: Collagen colitis (CC) is a microscopic colitis diagnosed by mucosal biopsy and is extremely rare in children., Patient Concerns: We reported a child with severe persistent diarrhea that could not be relieved with traditional diarrheal treatment. No abnormalities were found after multiple colonoscopies., Diagnoses: A significant increase in total IgE levels was found in the patient's blood. He had a history of mild chronic allergic rhinitis and slightly intermittent wheezing. However, we found that the child had a hyperallergic reaction to multiple respiratory antigens and had mild pulmonary dysfunction. Finally, colonoscopy with biopsy identified the diagnosis of CC., Intervention: Considering that a respiratory allergic reaction was one of the causes of diarrhea, anti-allergic treatment was given to the child, and his severe diarrhea was soon relieved. Corticosteroid treatment was suggested to the patient, but his parents firmly refused steroid therapy. According to the patient's specific allergic reaction to mites, desensitization treatment was finally chosen for him., Outcomes: After 1 year of desensitization for dust mites, the patient's respiratory symptoms improved, total IgE levels decreased, autoantibodies declined, and diarrhea did not reoccur. Colonoscopy with biopsy showed a significant improvement in pathology., Conclusion: CC in children is rare, and childhood CC induced by a respiratory allergic reaction has not been previously reported. Therefore, this is a special case of CC in a patient who was cured with anti-allergy treatments and desensitization instead of steroid therapy.

Introduction: Most children with eosinophilic esophagitis (EoE) are atopic, but the impact of atopy on the remission and development of EoE is still unclear. The aim of our study was to determine the impact of atopy on remission of EoE and to describe allergy tests and the choice of treatment for a cohort of EoE children in France., Methods: All children diagnosed with EoE between January 2013 and June 2018 in the five pediatric centers in the northeast of France were included. Children were divided into two groups according to personal atopic disorders. Histological remission was defined on the basis of an eosinophilic count below 15 eosinophils per high-power field., Results: Among the 49 children included, 38 (78%) were atopic. Allergy tests were performed for 45 children (92%). Rates of sensitization were similar in both groups: 64% had food sensitization and 64% had aeroallergen sensitization. The most commonly attempted first-line therapy was with proton pump inhibitors (63%), followed by swallowed topical steroids (STS) (18%). First-line therapy was not associated with atopic status (P=0.88). Atopic children had a nonsignificant tendency for a higher remission rate after STS (55% vs. 0%, P=0.24) and a higher global remission rate (54% vs. 33%, P=0.18) compared with non-atopic children., Conclusion: Allergy testing is relevant in the majority of children with EoE whether or not they have atopic disorders. Atopy seems to be associated with better response to STS. Further studies are needed to determine whether atopic status determines histological response., (Copyright © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Chronic cough is one of the most common complaints for which patients in China seek medical attention. However, there are no nationwide data on the prevalence and socioeconomic burden of chronic cough. Although approximately 50% of Chinese men smoke, the vast majority of patients presenting for evaluation of chronic cough are never smokers. An equal sex distribution and a middle-aged predominance have been observed in the Chinese chronic cough population, despite demonstration of a higher cough reflex sensitivity in females and older patients. The role of air pollution in the distinct age and sex distribution requires further study. In terms of the etiologies of chronic cough in China, cough-variant asthma, upper airway cough syndrome, nonasthmatic eosinophilic bronchitis, and atopic cough are the most common causes, comprising 75.2% to 87.6% of cases across different regions. Chinese Guidelines for Diagnosis and Treatment of Cough were initially published in 2005, and updated in 2009 and 2016. In addition, the China Cough Coalition was established in 2016. Great progress has been made in both cough-related clinical practice and research in recent years, however, there are still challenges ahead. To facilitate optimal management of chronic cough in China, efforts promoting the dissemination and application of published guidelines will be essential, especially in community-based healthcare and in rural regions. As chronic refractory cough has been identified as a huge challenge to clinicians worldwide, continued international cooperation will be essential in optimizing evaluation and management of chronic cough.

We measured the effect of Rho-kinase on inflammation and mucus hypersecretion in the airways of mouse models of asthma. Additionally, we aimed to determine if these effects were the result of JNK 1/2-AP1 pathway inhibition.We sensitized and challenged female C57BL/6 mice using house dust mites (HDM) followed by treatment with an inhibitor of Rho-kinase. Lung tissue was harvested to evaluate inflammation and mucus secretion in the airways of asthma mice. Cytokine expression in broncho-alveolar lavage fluid (BALF) was established by ELISA and airway responsiveness, and was determined by the invasive lung function test. JNK1/2, p-JNK1/2, AP-1, and p-AP-1 protein expression was determined by Western blot analysis. Asthma model mice that were treated with Rho-kinase inhibitor showed a significantly decrease in inflammation score, inflammatory cells, and airway responsiveness. Additionally, we found that IL-13 expressions in BALF and mucus secretion were decreased in HDM-challenged mice treated with Rho-kinase inhibitor. Furthermore, Rho-kinase inhibitor treatment decreased the expression of JNK1/2 and AP-1 phosphorylation. Our findings indicated that the Rho-kinase inhibitor decreased HDM-induced mucus secretion as well as airway inflammation in asthma mice through regulation of the JNK1/2-AP-1 pathway., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Resveratrol (RSV) has attracted interest as an alternative drug for the treatment of acute lung injury (ALI) and other pulmonary diseases, but its poor oral bioavailability is a limitation. In this study, we employed drug delivery nanotechnology to improve the stability, lung localization and efficacy of orally administered resveratrol to control lung damage leading to ALI., Methods and Materials: RSV-loaded lipid-core nanocapsules (RSV-LNCs), prepared by interfacial deposition of biodegradable polymers, were given orally to A/J mice prior to lipopolysaccharide (LPS) intranasal instillation. Inflammatory changes, oxidative stress and lung tissue elastance were assessed 24 h after LPS challenge., Results: RSV-LNCs (5 mg/kg), given 1, 4, 6 or 12 h but not 24 h before provocation, inhibited LPS-induced leukocyte accumulation in the bronchoalveolar fluid (BALF), whereas unloaded nanocapsules (ULNCs) or free RSV (5 mg/kg) were ineffective. RSV-LNCs (2.5-10 mg/kg) but not ULNCs or RSV improved lung function and prevented total leukocyte and neutrophil accumulation equally in both BALF and lung tissue when given 4 h before LPS challenge. Similar findings were seen concerning the generation of a range of pro-inflammatory cytokines such as IL-6, KC, MIP-1α, MIP-2, MCP-1 and RANTES in lung tissue. In addition, only RSV-LNCs inhibited MDA levels and SOD activity in parallel with blockade of the ERK and PI3K/Akt pathways following LPS provocation., Conclusion: Nanoformulation of RSV in biodegradable oil-core polymers is an effective strategy to improve the anti-ALI activity of RSV, suggesting that the modified-release formulation of this plant polyphenol may be of great value in clinical conditions associated with ALI and respiratory failure., Competing Interests: MTP de Oliveira and DS Coutinho were fellows from CAPES. ET de Souza was the recipient of a FAPERJ postdoctoral fellowship. The authors report no other conflicts of interest related to this work.

Background: Environmental tobacco smoke (ETS) is a known risk factor for severe respiratory syncytial virus (RSV) infections, yet the mechanisms of ETS/RSV comorbidity are largely unknown. Cystathionine γ-lyase regulates important physiological functions of the respiratory tract., Methods: We used mice genetically deficient in the cystathionine γ-lyase enzyme (CSE), the major H 2 S-generating enzyme in the lung to determine the contribution of H 2 S to airway disease in response to side-stream tobacco smoke (TS), and to TS/RSV co-exposure., Results: Following a 2-week period of exposure to TS, CSE-deficient mice (KO) showed a dramatic increase in airway hyperresponsiveness (AHR) to methacholine challenge, and greater airway cellular inflammation, compared with wild-type (WT) mice. TS-exposed CSE KO mice that were subsequently infected with RSV exhibited a more severe clinical disease, airway obstruction and AHR, enhanced viral replication, and lung inflammation, compared with TS-exposed RSV-infected WT mice. TS-exposed RSV-infected CSE KO mice had also a significant increase in the number of neutrophils in bronchoalveolar lavage fluid and increased levels of inflammatory cytokines and chemokines., Conclusion: This study demonstrates the critical contribution of the H 2 S-generating pathway to airway reactivity and disease following exposure to ETS alone or in combination with RSV infection.

Background: Most patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD) suffer from recurrence of nasal polyps. However, little is known about the specific cellular and molecular mechanisms contributing to the pathogenesis of nasal polyp development in patients with NERD in particular, especially at baseline when cyclooxygenase 1 inhibitors are not present. The objectives of this study were to identify proteins involved in the pathogenesis of nasal polyps in patients with NERD., Methods: We collected nasal polyp tissue from patients with NERD and from patients with aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP). Protein profiles were analyzed by 2-dimensional electrophoresis and identified several proteins, including L-plastin, as highly expressed. We examined L-plastin and tissue factor (TF) expression by immunohistochemical and immunofluorescence analyses. To examine the role of L-plastin in eosinophils, we knocked down L-plastin expression in Eol-1 cells by using siRNA transfection., Results: L-plastin protein levels in nasal polyp tissue were increased in patients with NERD relative to those in patients with aspirin tolerant CRSwNP. Immunofluorescence analysis revealed that L-plastin was dominantly expressed in eosinophils and L-plastin and TF were co-expressed in eosinophils in NERD nasal polyp tissue. Knockdown of L-plastin in Eol-1 cells disrupted the cell surface distribution of TF by stimulation with granulocyte macrophage colony-stimulating factor., Conclusion: Increased expression of L-plastin by eosinophils may contribute to abnormal fibrin deposition through TF translocation to the eosinophil cell surface in NERD nasal polyp tissue, which in turn may contribute to the pathogenesis of NERD., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Licochalcone A was isolated from Glycyrrhiza uralensis and previously reported to have antitumor and anti-inflammatory effects. Licochalcone A has also been found to inhibit the levels of Th2-associated cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. However, the molecular mechanism underlying airway inflammation and how licochalcone A regulates oxidative stress in asthmatic mice are elusive. In this study, we investigated whether licochalcone A could attenuate inflammatory and oxidative responses in tracheal epithelial cells, and whether it could ameliorate oxidative stress and airway inflammation in asthmatic mice. Inflammatory human tracheal epithelial (BEAS-2B) cells were treated with licochalcone A to evaluate oxidative responses and inflammatory cytokine levels. In addition, BALB/c mice were sensitized with ovalbumin (OVA) and injected intraperitoneally with licochalcone A (5 or 10 mg/kg). Licochalcone A significantly inhibited reactive oxygen species, eotaxin, and proinflammatory cytokines in BEAS-2B cells. Licochalcone A also decreased intercellular adhesion molecule 1 levels in inflammatory BEAS-2B cells, blocking monocyte cell adherence. We also found that licochalcone A significantly decreased oxidative responses, reduced malondialdehyde levels, and increased glutathione levels in the lungs of OVA-sensitized mice. Furthermore, licochalcone A decreased airway hyper-responsiveness, eosinophil infiltration, and Th2 cytokine production in the BALF. These findings suggest that licochalcone A alleviates oxidative stress, inflammation, and pathological changes by inhibiting Th2-associated cytokines in asthmatic mice and human tracheal epithelial cells. Thus, licochalcone A demonstrated therapeutic potential for improving asthma.

Importance: Rhinovirus infection in early life, particularly with allergic sensitization, is associated with higher risks of developing recurrent wheeze and asthma. While emerging evidence links different rhinovirus species (eg, rhinovirus C) to a higher severity of infection and asthma exacerbation, to our knowledge, little is known about longitudinal associations of rhinovirus C infection during infancy with subsequent morbidities., Objective: To examine the association of different viruses (respiratory syncytial virus [RSV], rhinovirus species) in bronchiolitis with risks of developing recurrent wheeze., Design, Setting, and Participants: This multicenter prospective cohort study of infants younger than 1 year who were hospitalized for bronchiolitis was conducted at 17 hospitals across 14 US states during 3 consecutive fall to winter seasons (2011-2014)., Exposures: Major causative viruses of bronchiolitis, including RSV (reference group) and 3 rhinovirus species (rhinovirus A, B, and C)., Main Outcomes and Measures: Development of recurrent wheeze (as defined in national asthma guidelines) by age 3 years., Results: This analytic cohort comprised 716 infants who were hospitalized for RSV-only or rhinovirus bronchiolitis. The median age was 2.9 months (interquartile range, 1.6-3.8 months), 541 (76%) had bronchiolitis with RSV only, 85 (12%) had rhinovirus A, 12 (2%) had rhinovirus B, and 78 (11%) had rhinovirus C infection. Overall, 231 (32%) developed recurrent wheeze by age 3 years. In the multivariable Cox model, compared with infants with RSV-only infection, the risk of recurrent wheeze was not significantly different in those with rhinovirus A or B (rhinovirus A: hazard ratio [HR], 1.27; 95% CI, 0.86-1.88; rhinovirus B: HR, 1.39; 95% CI, 0.51-3.77; both P > .10). By contrast, infants with rhinovirus C had a significantly higher risk (HR, 1.58; 95% CI, 1.08-2.32). There was a significant interaction between virus groups and IgE sensitization on the risk of recurrent wheeze (P for interaction < .01). Only infants with both rhinovirus C infection and IgE sensitization (to food or aeroallergens) during infancy had significantly higher risks of recurrent wheeze (HR, 3.03; 95% CI, 1.20-7.61). Furthermore, compared with RSV-only, rhinovirus C infection with IgE sensitization was associated with significantly higher risks of recurrent wheeze with subsequent development of asthma at age 4 years (HR, 4.06; 95% CI, 1.17-14.1)., Conclusions and Relevance: This multicenter cohort study of infants hospitalized for bronchiolitis demonstrated between-virus differences in the risk of developing recurrent wheeze. Infants with rhinovirus C infection, along with IgE sensitization, had the highest risk. This finding was driven by the association with a subtype of recurrent wheeze: children with subsequent development of asthma.

Platelets modulate asthma pathogenesis by forming the platelet-eosinophil aggregation (PEA), which facilitates the activation of eosinophils. Platelets exhibit the purinergic receptor (P2Y12R), which responds to cysteinyl leukotriene E4 (LTE 4 ). We have suggested that the combination of an antiplatelet drug (clopidogrel, [Clo]) and montelukast (Mon) would synergistically suppress asthma. BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) on days 0 and 14 and subsequently challenged on days 28-30 and 42-44. Mice were administered with Clo (10 mg/kg), Mon (10 mg/kg) or both drugs (Clo/Mon) orally 30 minutes before the OVA (1%) challenge on days 42-44. Mice were assayed for airway hyper-responsiveness (AHR) to methacholine and airway inflammation. Clopidogrel and montelukast attenuated the increased AHR; the combined treatment was more effective than a single treatment for total and eosinophil counts (all P < 0.05). Levels of interleukin (IL)-4, IL-5, IL-13, platelet factor 4, eosinophil peroxidase and LTE 4 increased in the bronchoalveolar lavage fluid of asthmatic mice, but these levels decreased in mice treated with Clo/Mon (all P < 0.05). Goblet cell hyperplasia decreased in response to Clo/Mon. Mouse platelets and eosinophils were isolated and co-cultured for an in vitro assay with 10 µmol/L adenosine diphosphate (ADP), LTE 4 (200 nmol/L), Mon (1 µmol/L), Clo (1 µmol/L) and Clo/Mon (1 µmol/L). Flow cytometry revealed that the increased formation of the PEA (%) was fully mediated by ADP and partly mediated by LTE 4 . Clo/Mon reduced ADP-induced PEA formation and P-selectin expression (P < 0.05). In conclusion, Clo/Mon synergistically relieved asthma by inhibiting ADP-mediated PEA formation., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Interleukin (IL)-37 has been described as a negative regulator of immune responses and is critical for asthma pathogenesis, but the mechanisms behind the protective role of IL-37 against allergic asthma are less well understood. We show here that IL-37 administered intranasally inhibited house dust mite (HDM)-induced chronic airway eosinophilic inflammation, goblet cell hyperplasia, peribronchial collagen deposition and airway hyperresponsiveness (AHR) to methacholine. In contrast to a weakened Th2 response in the lung that was characterized by the downregulation of Th2-associated cytokines and chemokines in IL-37-treated mice, IL-37 has no effect on relevant markers of systemic Th2 immune including serum immunoglobulins expression and in vitro production of Th2-associated cytokines by splenocytes on HDM recall. We demonstrated that the production of thymic stromal lymphopoietin (TSLP) in the lung tissue was associated with IL-37. Importantly, compared with IL-37 alone, TSLP coadministration with IL-37 restored HDM-induced airway inflammation and structural alterations, increased AHR to methacholine and promoted Th2-associated cytokine production. We further found that IL-37 inhibited the induction of TSLP expression by the main antigen of house dust mite, Der p1, by suppressing NF-κB and extracellular signal regulated kinase 1/2 (ERK1/2) activation in human bronchial epithelial (16-HBE) cells in vitro. These data highlight the importance of TSLP in IL-37-mediated protective role in asthma. IL-37 might represent a useful innovative and alternative therapy to control TSLP production in the airway., (© 2018 Australasian Society for Immunology Inc.)

In the general population, particularly in individuals with asthma, cough is a common symptom, often reported after exertion, although regular exercise may be associated with a reduction in the prevalence of cough. In athletes, exercise-induced cough is also a particularly frequent symptom. The main etiologies of cough in athletes are somewhat similar to non-athletes, including asthma/airway hyperresponsiveness, upper airways disorders such as allergic or non-allergic rhinitis, and exercise-induced laryngeal obstruction, although these conditions are more frequently observed in athletes. In these last, this symptom can also be related to the high ventilation and heat exchange experienced during exercise, particularly during exposure to cold/dry air or pollutants. However, gastroesophageal reflux, a common cause of cough in the general population, despite being highly prevalent in athletes, has not been reported as a main cause of cough in athletes. Cough may impair quality of life, sleep and exercise performance in the general population and probably also in athletes, although there are few data on this. The causes of cough should be documented through a systematic evaluation, the treatment adapted according to identified or most probable cough etiology and pattern of presentation, while respecting sports anti-doping regulations. More research is needed on exercise-induced persistent cough in the athlete to determine its pathophysiology, optimal management and consequences., (Copyright © 2019. Published by Elsevier Ltd.)

Our previous study showed that neonatal S. pneumoniae infection aggravated airway inflammation and airway hyperresponsiveness (AHR) in an OVA-induced allergic asthma model. As airway smooth muscle (ASM) plays a pivotal role in AHR development, we aim to investigate the effects of neonatal S. pneumoniae pneumonia on ASM structure and AHR development. Non-lethal neonatal pneumonia was established by intranasally infecting 1-week-old BALB/C mice with the S. pneumoniae strain D39. Five weeks after infection, the lungs were collected to assess the levels of α -SMA and the contractile proteins of ASM. Our results indicate that neonatal S. pneumoniae pneumonia significantly increased adulthood lung α -SMA and SMMHC proteins production and aggravated airway inflammatory cells infiltration and cytokines release. In addition, the neonatal S. pneumoniae pneumonia group had significantly higher Penh values compared to the uninfected controls. These data suggest that neonatal S. pneumoniae pneumonia promoted an aberrant ASM phenotype and AHR development in mice model.

In asthma, airway nerve dysfunction leads to excessive bronchoconstriction and cough. It is well established that eosinophils alter nerve function and that airway eosinophilia is present in 50 to 60% of asthmatics. However, the effects of eosinophils on airway nerve structure have not been established. We tested whether eosinophils alter airway nerve structure and measured the physiological consequences of those changes. Our results in humans with and without eosinophilic asthma showed that airway innervation and substance P expression were increased in moderate persistent asthmatics compared to mild intermittent asthmatics and healthy subjects. Increased innervation was associated with a lack of bronchodilator responsiveness and increased irritant sensitivity. In a mouse model of eosinophilic airway inflammation, the increase in nerve density and airway hyperresponsiveness were mediated by eosinophils. Our results implicate airway nerve remodeling as a key mechanism for increased irritant sensitivity and exaggerated airway responsiveness in eosinophilic asthma., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthmatic patients, there is still very little known about the pathophysiologic mechanisms involved. Plasmacytoid dendritic cells (pDCs), prominent cells of antiviral immunity, exhibit proinflammatory or tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored., Objectives: We sought to investigate the role of pDCs in allergic airway inflammation and acute asthma exacerbations., Methods: Animal models of allergic airway disease (AAD) and virus-induced AAD exacerbations were used to dissect pDC function in vivo and unwind the potential mechanisms involved. Sputum from asthmatic patients with stable disease or acute exacerbations was further studied to determine the presence of pDCs and correlation with inflammation., Results: pDCs were key mediators of the immunoinflammatory cascade that drives asthma exacerbations. In animal models of AAD and rhinovirus-induced AAD exacerbations, pDCs were recruited to the lung during inflammation and migrated to the draining lymph nodes to boost T H 2-mediated effector responses. Accordingly, pDC depletion after allergen challenge or during rhinovirus infection abrogated exacerbation of inflammation and disease. Central to this process was IL-25, which was induced by allergen challenge or rhinovirus infection and conditioned pDCs for proinflammatory function. Consistently, in asthmatic patients pDC numbers were markedly increased during exacerbations and correlated with the severity of inflammation and the risk for asthma attacks., Conclusions: Our studies uncover a previously unsuspected role of pDCs in asthma exacerbations with potential diagnostic and prognostic implications. They also propose the therapeutic targeting of pDCs and IL-25 for the treatment of acute asthma., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Various allergenic proteins are produced by house dust mites (HDM). However, the allergenicity and clinical implications of these allergens are unknown., Objective: The purpose of this study was to identify allergens in Dermatophagoides farinae and elucidate the sensitization profiles to these in Korean patients suffering from respiratory (allergic rhinitis and/or asthma) and atopic dermatitis symptoms., Methods: IgE reactivities in sera from 160 HDM allergy patients were analysed by one- and two-dimensional gel electrophoresis and immunoblotting. IgE-reactive components were identified by liquid chromatography-coupled electrospray ionization-tandem mass spectrometry. Nine recombinant mite allergens (Der f 1, Der f 2, Der f 10, Der f 11, Der f 13, Der f 14, Der f 30, Der f 32 and Der f Alt a 10) were produced, and the IgE reactivity in sera to each was determined by ELISAs., Results: Der f 1 and Der f 2 were recognized by IgE in serum samples from 88.1% and 78.1% of all patients, respectively. Patients with respiratory allergies were mainly sensitized to these major allergens, whereas patients with atopic dermatitis symptoms showed polysensitization to major and minor allergen components (including Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10)., Conclusions: Patients with respiratory allergic disease sensitize to major allergen components of HDM. Those with atopic dermatitis were sensitized to a broader range of minor allergen components of HDM (Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10)., (© 2018 John Wiley & Sons Ltd.)

Objective: To investigate the effects of ligustrazine (LTZ) on airway inflammation in a mouse model of neutrophilic asthma (NA)., Methods: Forty healthy C57BL/6 female mice were randomly divided into 4 groups using a random number table, including the normal control, NA, LTZ and dexamethasone (DXM) groups, with 10 rats in each group. The NA mice model was established by the method of ovalbumin combined with lipopolysaccharide sensitization. At 0.5 h before each challenge, LTZ and DXM groups were intraperitoneally injected with LTZ (80 mg/kg) or DXM (0.5 mg/kg) for 14 d, respectively, while the other two groups were given the equal volume of normal saline. After last challenge for 24 h, the aerosol inhalation of methacholine was performed and the airway reactivity was measured. The bronchoalveolar lavage fluid (BALF) was collected. The Wright-Giemsa staining was used for total white blood cells and differential counts. The levels of cytokines interleukin (IL)-17 and IL-10 were detected by enzyme-linked immunosorbent assay. The pathological change of lung tissue was observed by hematoxylin eosin staining., Results: The airway responsiveness of the NA group was signifificantly higher than the normal control group (P<0.05), while those in the LTZ and DXM groups were signifificantly lower than the NA group (P<0.05). The neutrophil and eosinophil counts in the LTZ and DXM groups were signifificantly lower than the NA group (P<0.05), and those in the LTZ group were signifificantly lower than the DXM group (P<0.05). There were a large number of peribronchiolar and perivascular inflammatory cells in fifiltration in the NA group. The airway inflflammation in the LTZ and DXM groups were signifificantly alleviated than the NA group. The infifiltration in the LTZ group was signifificantly reduced than the DXM group. Compared with the normal control group, the IL-17 level in BALF was signifificantly increased and the IL-10 level in BALF was signifificantly decreased in the NA group (P<0.05). LTZ and DXM treatment signifificantly decreased IL-17 levels and increased IL-10 levels compared with the NA group (P<0.05), and the changes in the above indices were more signifificant in the LTZ group (P<0.05)., Conclusion: LTZ could alleviate the airway inflflammation in the NA mice model through increasing the IL-10 level and decreasing the IL-17 level.

Objectives: Asthma is a chronic inflammatory airway disease characterized by reversible airway constriction and airway hyperresponsiveness. Asthma is a worldwide problem and its prevalence varies among different parts of the world. There are insufficient data about the prevalence and risk factors of this disease in Middle East countries., Data Source: The objective of this review article was to determine the prevalence of asthma in Middle East countries by searching EMBASE, Medline, Web of Science and Google Scholar for articles about asthma prevalence in children and adults in this region., Study Selection: The prevalence of asthma in different countries and different cities of each country in the Middle East was reviewed in children and adults of both sexes. The possible risk factors for asthma in different areas were also reviewed from 1985 to 2012., Results: The highest asthma prevalence in children and adults was 35.4% in Tehran, Iran by ISAAC phase I and 15% in Kuwait by self-designed questionnaire and the lowest prevalence was 1% in Kermanshah, Iran by ISAAC and 2% in Tehran, Iran by ECRHS questionnaire, respectively. Most studies showed that the prevalence of this common disease declines with increasing age., Conclusion: The data showed that the prevalence of asthma varies among different countries and even among different cities of the same country. The common risk factors for this disease were genetic predisposition, cigarette smoking, family history of asthma and allergic diseases., (© 2017 John Wiley & Sons Ltd.)

Asthma is a chronic disease related to airway hyperresponsiveness and airway remodeling. Airway remodeling is the important reason of refractory asthma and is associated with differentiation of airway epithelia into myofibroblasts via epithelial-mesenchymal transition (EMT) to increase the process of subepithelial fibrosis. There is growing evidence that autophagy modulates remodeling. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we hypothesized that Follistatin-like 1 (FSTL1) promotes EMT and airway remodeling by intensifying autophagy. With the use of transmission electron microscopy (TEM), double-membrane autophagosomes were detected in the airways of patients and mice. More autophagosomes were in patients with asthma and OVA-challenged mice compared with healthy controls. The expression of FSTL1 and beclin-1 was upregulated in the airways of patients with asthma and OVA-challenged mice, accompanied by airway EMT and remodeling. In OVA-challenged Fstl1 +/- mice, the degree of airway remodeling and autophagy was decreased compared with control mice. The effects of FSTL1 on autophagy and EMT were also tested in 16HBE cells in vitro. Additionally, inhibition of autophagy by using LY-294002 and siRNA-ATG5 reduced the FSTL1-induced EMT in 16HBE cells, as measured by E-cadherin, N-cadherin, and vimentin expression. In line herewith, administration of LY-294002 reduced the expression of autophagy, EMT, and airway remodeling markers in FSTL1-challenged WT mice. Taken together, our study suggests that FSTL1 may induce EMT and airway remodeling by activating autophagy. These findings may provide novel avenues for therapeutic research targeting the autophagy and FSTL1 pathway, which may be beneficial to patients with refractory asthma., (Copyright © 2017 the American Physiological Society.)

Electronic cigarette usage is increasing worldwide, yet there is a paucity of information on the respiratory health effects of electronic cigarette aerosol exposure. This study aimed to assess whether exposure to electronic cigarette (e-cigarette) aerosol would alter lung function and pulmonary inflammation in mice and to compare the severity of any alterations with mice exposed to mainstream tobacco smoke. Female BALB/c mice were exposed for 8 wk to tobacco smoke, medical air (control), or one of four different types of e-cigarette aerosol. E-cigarette aerosols varied depending on nicotine content (0 or 12 mg/ml) and the main excipient (propylene glycol or glycerin). Twenty-four hours after the final exposure, we measured pulmonary inflammation, lung volume, lung mechanics, and responsiveness to methacholine. Mice exposed to tobacco cigarette smoke had increased pulmonary inflammation and responsiveness to methacholine compared with air controls. Mice exposed to e-cigarette aerosol did not have increased inflammation but did display decrements in parenchymal lung function at both functional residual capacity and high transrespiratory pressures. Mice exposed to glycerin-based e-cigarette aerosols were also hyperresponsive to methacholine regardless of the presence or absence of nicotine. This study shows, for the first time, that exposure to e-cigarette aerosol during adolescence and early adulthood is not harmless to the lungs and can result in significant impairments in lung function., (Copyright © 2017 the American Physiological Society.)

Children with atopic dermatitis (AD) usually develop symptoms when they reach the age of 6-7 years, but the risk of developing respiratory allergies, asthma and allergic rhinitis (AR) remains high. In most children with AD, the development of asthma and AR is associated with sensitization to food allergens and/or aeroallergens, while only a small percentage missed atopic diathesis. In about 35% of children with AD, food allergy is the provoking cause, and 60% of infants who had AD in the first 3 months of life were sensitized against aeroallergens by the age of 5. The aim of the study was to follow development of asthma and AR and to assess the most significant risk factors for developing respiratory allergy. A total of 114 children with AD were followed up for five years. At annual visits, the severity of disease, total immunoglobulin E (IgE) antibody values, skin prick tests, specific IgE antibodies to food allergens and aeroallergens, and absolute eosinophil count were assessed. Information on the family history of atopy and AD, feeding patterns during infancy, data on sensitivity to food allergens and/or aeroallergens, and on the occurrence of bronchial obstruction and nose symptoms were obtained. Asthma developed in 36 children, median age 7.7 years; 33 children had symptoms of AR, and 13 children with AD had both diseases associated; 38 children had sensitivity to food, of which 24 developed asthma and 13 AR; asthma developed in 18/23 children with sensitivity to aeroallergens, and almost an equal number of children developed AR. The increased absolute eosinophil count and specific IgE to aeroallergens and food allergens were the best asthma predictors, while AR predictors were family history and early onset of AD. In conclusion, children with AD are at a significant risk of developing respiratory allergies, and those with the increased absolute eosinophil count, positive specific IgE to aeroallergens and food allergens, heredity of AD, and early onset of AD are at the highest risk. Identification of risk factors will enable us to improve the treatments of AD in order to reduce the severity of disease and prevent manifestation of respiratory allergy.

Respiratory syncytial virus (RSV)-related hospitalization during infancy is strongly associated with the subsequent development of asthma. Early life RSV infection results in a Th2-biased immune response, which is also typical of asthma. Murine models of neonatal RSV infection have been developed to examine the possible contribution of RSV-driven Th2 responses to the development of airway hyper-responsiveness later in childhood. We have investigated the ability of a cell-penetrating STAT6 inhibitory peptide (STAT6-IP), when delivered selectively during neonatal RSV infection, to modify pathogenesis induced upon secondary RSV reinfection of adults 6 wk later. Neonatal STAT6-IP treatment inhibited the development of airway hyper-responsiveness (AHR) and significantly reduced lung eosinophilia and collagen deposition in adult mice following RSV reinfection. STAT6-IP-treated, RSV-infected neonates had reduced levels of both IL-4 and alternatively activated macrophages (AAMs) in the lungs. Our findings suggest that targeting STAT6 activity at the time of early-life RSV infection may effectively reduce the risk of subsequent asthma development., (© Society for Leukocyte Biology.)

Acute exacerbation of interstitial pneumonia is a new terminology with recent debated criteria. Its prognosis is bad and its management remains non consensual. This lack of consensus seems to be due to the lack of knowledge concerning the physiopathologic phenomenon. This lack of knowledge results in few efficient therapeutics. The diagnosis of acute exacerbation is challenging for clinicians and the real place of the pathologic exam remains unknown. Our aim was to assess the different situations faced by the pathologists by emphasizing their real role.

Background: The Sinonasal Outcome Test (SNOT-22) has been used as a patient reported outcome measure to grade symptom severity before and after treatment for chronic rhinosinusitis (CRS)., Methodology: This analysis uses data from the CRS Epidemiology Study (CRES). The overarching aim of CRES was to determine factors that influence the onset and severity of CRS. A study-specific questionnaire including SNOT-22 was distributed to patients with CRS attending ENT clinics across 30 centres in the United Kingdom. The aim of this analysis was to compare SNOT-22 scores between those with different types of CRS to determine any differences present in the total score or the subdomains and to assess whether any differences varied according to gender., Results: There were a total of 1249 CRS participants in the following subgroups: CRS without nasal polyps (CRSsNPs) (n=553), CRS with nasal polyps (CRSwNPs) (n=651), allergic fungal rhinosinusitis (AFRS) (n=45). Since there were differing gender ratios in each subgroup, males and females were analysed separately. The mean and standard deviation for SNOT-22 was: males CRSsNP 41.1 (21.0), CRSwNP 41.7 (20.5); females CRSsNP 49.6 (19.7), CRSwNP 49.5 (22.9). In the nasal domain, those with CRSwNP scored more highly than those with CRSsNP; for males 18.1 (8.1) vs. 15.9 (7.9); for females 19.6 (8.0) vs 16.7 (7.5)., Conclusions: Patients with CRSwNPs report higher symptom scores in the nasal domain of SNOT-22 than those with CRSsNPs with women in both subgroups reporting higher total scores than men.

The role of seasons should be taken into account in the management of asthma. The environment varies between seasons and it is well documented that asthma is modulated by environment. Viruses cause asthma exacerbations peak, in winter, in adults while the peak is present in September in children. Allergens are probably a less powerful source of asthma exacerbation than viruses but pollen involvement in spring and summer and dust mites in autumn are indisputable. Air pollutants, present in summer during the hottest periods, are also highly involved in asthma exacerbations. Indoor air pollution, in winter, is also implicated in asthma disease. All these environmental factors are synergistic and increase the risk of asthma exacerbation. Therapies should be adapted to each season depending on environmental factors potentially involved in the asthma disease., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Triggers and precipitating factors as well as comorbid conditions are associated with asthma and severe asthma. They interfere with the potential to control the disease and represent an additional burden for the patients. Allergen exposure is well known to induce loss of control and exacerbations. Comorbid conditions belong to various fields of medicines including cardiovascular diseases, osteoporosis, obesity and sleep apneas and GERD. They should be diagnosed and treated for themselves according to the best state of the art. Their precise role et their contribution to severe asthma pathophysiology is largely unknown and longitudinal cohort studies are needed to better understand and treat the patients with severe asthma., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Bronchopulmonary dysplasia (BPD) is characterized by lifelong obstructive lung disease and profound, refractory bronchospasm. It is observed among survivors of premature birth who have been treated with prolonged supplemental oxygen. Therapeutic options are limited. Using a neonatal mouse model of BPD, we show that hyperoxia increases activity and expression of a mediator of endogenous bronchoconstriction, S-nitrosoglutathione (GSNO) reductase. MicroRNA-342-3p, predicted in silico and shown in this study in vitro to suppress expression of GSNO reductase, was decreased in hyperoxia-exposed pups. Both pretreatment with aerosolized GSNO and inhibition of GSNO reductase attenuated airway hyperresponsiveness in vivo among juvenile and adult mice exposed to neonatal hyperoxia. Our data suggest that neonatal hyperoxia exposure causes detrimental effects on airway hyperreactivity through microRNA-342-3p-mediated upregulation of GSNO reductase expression. Furthermore, our data demonstrate that this adverse effect can be overcome by supplementing its substrate, GSNO, or by inhibiting the enzyme itself. Rates of BPD have not improved over the past two decades; nor have new therapies been developed. GSNO-based therapies are a novel treatment of the respiratory problems that patients with BPD experience., (Copyright © 2016 by The Author(s).)

Mesenchymal stem cell (MSC) immunosuppressive functions make them attractive candidates for anti-inflammatory therapy in allergic asthma. However, the mechanisms by which they ensure therapeutic effects remain to be elucidated. In an acute mouse model of house dust mite (Der f)-induced asthma, one i.v. MSC injection was sufficient to normalize and stabilize lung function in Der f-sensitized mice as compared to control mice. MSC injection decreased in vivo airway responsiveness and decreased ex vivo carbachol-induced bronchial contraction, maintaining bronchial expression of the inhibitory type 2 muscarinic receptor. To evaluate in vivo MSC survival, MSCs were labeled with PKH26 fluorescent marker prior to i.v. injection, and 1 to 10 days later total lungs were digested to obtain single-cell suspensions. 91.5 ± 2.3% and 86.6 ± 6.3% of the recovered PKH26(+) lung cells expressed specific macrophage markers in control and Der f mice, respectively, suggesting that macrophages had phagocyted in vivo the injected MSCs. Interestingly, only PKH26(+) macrophages expressed M2 phenotype, while the innate PKH26(-) macrophages expressed M1 phenotype. Finally, the remaining 0.5% PKH26(+) MSCs expressed 10- to 100-fold more COX-2 than before injection, suggesting in vivo MSC phenotype modification. Together, the results of this study indicate that MSCs attenuate asthma by being phagocyted by lung macrophages, which in turn acquire a M2 suppressive phenotype. Stem Cells 2016;34:1836-1845., (© 2016 AlphaMed Press.)

Administration of human bone marrow-derived mesenchymal stem cells (BM-MSCs) significantly alleviates allergic airway inflammation. There are no studies that refer to the role of microRNAs (miRNAs) after the BM-MSCs treatment in airway allergic inflammation. We induced a mouse model of asthma and performed the transplantation of BM-MSCs. We analyzed aberrant miRNAs and key immune regulators using both miRNA and messenger RNA (mRNA) polymerase chain reaction (PCR) arrays. We identified that 296 miRNAs were differently expressed after the induction of asthma and/or the treatment of BM-MSCs, in which 14 miRNAs presented the reverse variation tendency between asthma induction and BM-MSCs transplantation. Mmu-miR-21a-3p, mmu-miR-449c-5p, and mmu-miR-496a-3p were further confirmed to be differently expressed with additional samples and quantitative real-time PCR. With an mRNA PCR array, we identified 19 genes to be involved in the allergy induction and the administration of BM-MSCs. Further target genes analysis revealed that mmu-miR-21a-3p was significantly correlated with the immune regulator activin A receptor, Type IIA (Acvr2a). Mmu-miR-21a-3p had opposite expression with Acvr2a after asthma and BM-MSCs treatment. Acvr2a had binding sites for miR-21a for both mice and human, suggesting that miR-21/Acvr2a axis is conserved between human and mice. Dual-luciferase reporter assay showed that mmu-miR-21a-3p negatively regulated the transcript of Acvr2a. In addition, has-miR-21a inhibitor significantly increased the expression of Acvr2a mRNA in BEAS-2B cells under lipopolysaccharide stimulation. Our results suggest that there were different miRNA and mRNA profiles after asthma induction and BM-MSCs treatment, and the miR-21/Acvr2a axis is an important mechanism for the induction of asthmatic inflammation.

Allergic asthma can be frequently caused and exacerbated by sensitization to ubiquitous fungal allergens associated with pulmonary mucus production, airway hyperresponsiveness and bronchial constriction, resulting in a complex disease that is often difficult to treat. Fungal infections are frequently complicated by the development of a type 2 immune response that prevents successful elimination of the fungal pathogen. Furthermore, production of type 2 cytokines triggers allergic airway inflammation. Following intranasal infection of BALB/c mice with the fungusCryptococcus neoformans, we recently described a more pronounced type 2 immune response in the absence of regulatory T (Treg) cells. To determine whether Treg cell expansion is able to suppress type 2-related fungal allergic inflammation, we increased Treg cell numbers during pulmonaryC. neoformansinfection by administration of an interleukin (IL)-2/anti-IL-2 complex. Expansion of Treg cells resulted in reduced immunoglobulin E production and decreased allergic airway inflammation including reduced production of pulmonary mucus and type 2 cytokines as well as production of immunosuppressive cytokines such as IL-10 and transforming growth factor-β1. From our data we conclude that Treg cells and/or their suppressive mediators represent potential targets for therapeutic intervention during allergic fungal airway disease., (© FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The effect of respiratory tract viral infection on evoked cough in guinea pigs was evaluated. Guinea pigs were inoculated intranasally with either parainfluenza type 3 (PIV3) and cough was quantified in conscious animals. The guinea pigs infected with PIV3 (day 4) coughed nearly three times more than those treated with the viral growth medium in response to capsaicin, citric acid, and bradykinin. Since capsaicin, citric acid, and bradykinin evoked coughing in guinea pigs can be inhibited by drugs that antagonize the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), it was reasoned that the virally-induced hypertussive state may involve alterations in TPRV1 activity. PIV3 infection caused a phenotypic switch in tracheal nodose Aδ "cough receptors" such that nearly 50% of neurons began to express, de novo, TRPV1 mRNA. There was also an increase TRPV1 expression in jugular C-fiber neurons as determined by qPCR. It has previously been reported that tracheal-specific nodose neurons express the BDNF receptor TrkB and jugular neurons express the NGF receptor TrkA. Jugular neurons also express the artemin receptor GFRα3. All these neurotrophic factors have been associated with increases in TRPV1 expression. In an ex vivo perfused guinea pig tracheal preparation, we demonstrated that within 8 h of PIV3 infusion there was no change in NGF mRNA expression, but there was nearly a 10-fold increase in BDNF mRNA in the tissue, and a small but significant elevation in the expression of artemin mRNA. In summary, PIV3 infection leads to elevations in TRPV1 expression in the two key cough evoking nerve subtypes in the guinea pig trachea, and this is associated with a hypertussive state with respect to various TRPV1 activating stimuli.

Obesity affects the incidence and severity of asthma in at least two major phenotypes: an early-onset allergic (EOA) form that is complicated by obesity and a late-onset nonallergic (LONA) form that occurs only in the setting of obesity. Both groups exhibit airway hyperresponsiveness to methacholine challenge but exhibit differential effects of weight loss. Measurements of lung function in patients with LONA obese asthma suggest that this group of individuals may simply be those unlucky enough to have airways that are more compliant than average, and that this leads to airway hyperresponsiveness at the reduced lung volumes caused by excess adipose tissue around the chest wall. In contrast, the frequent exacerbations in those with EOA obese asthma can potentially be explained by episodic inflammatory thickening of the airway wall synergizing with obesity-induced reductions in lung volume. These testable hypotheses are based on the strong likelihood that LONA and EOA obese asthma are distinct diseases. Both, however, may benefit from targeted therapeutics that impose elevations in lung volume.

Asthma is a common chronic respiratory disease. In a previous study, we found several circulating microRNA signatures associated with childhood asthma and selected miR-3162-3p for subsequent studies. Since the target proteins and underlying molecular mechanisms of miR-3162-3p in asthma etiopathogenesis are not well characterized, we designed this study to clarify its role. We employed bioinformatics and quantitative PCR methods as a first step to determine the target of miR-3162-3p, and we elucidated β-catenin. Luciferase assays and western blot analysis confirmed β-catenin as a direct target of miR-3162-3p as the 3'-untranslated region of β-catenin mRNA possesses a specific miR-3162-3p pairing site. The correlation between the expression levels of miR-3162-3p and β-catenin is confirmed by quantitative PCR and western blot studies in A549, Beas-2B and H1299 cell lines and OVA-induced asthma mouse model. Of note, upregulation of the endogenous miR-3162-3p level is concomitant with the reduction of β-catenin mRNA and protein expression levels. MiR-3162-3p antagomir treatment antagonizes the endogenous miR-3162-3p and effectively rescues the attenuation of endogenous β-catenin in OVA-induced asthmatic mice, which alleviates airway hyperresponsiveness and ameliorates airway inflammation. Collectively, our findings suggest a novel relationship between miR-3162-3p and β-catenin and clarify their mechanistic role in asthma etiopathogenesis.

Background & Aims: Although chronic cough is common, its etiology is often elusive, making patient management a challenge. Gastroesophageal reflux and airway hypersensitivity can cause chronic cough. We explored the relationship between reflux, phonation, and cough in patients with idiopathic chronic cough., Methods: We performed a blinded, cross-sectional study of nonsmoking patients with chronic cough (duration, >8 weeks) refractory to reflux treatment referred to the Digestive Disease Center at Vanderbilt University. All underwent 24-hour acoustic recording concurrently and temporally synchronized with ambulatory pH-impedance monitoring. Cough, phonation, and pH-impedance events were recorded. We evaluated the temporal relationship between cough and phonation or reflux events using Poisson and logistic regression., Results: Seventeen patients met the inclusion criteria (88% female; 100% white; median age, 63 years [interquartile age range, 52-66 years]; mean body mass index, 30.6 [interquartile range, 27.9-34.0]); there were 2048 analyzable coughing events. The probability of subsequent coughing increased with higher burdens of preceding cough, reflux, or phonation. Within the first 15 minutes after a cough event, the cough event itself was the main trigger of subsequent cough events. After this period, de novo coughing occurred with increases of 1.46-fold in association with reflux alone (95% confidence interval, 1.17-1.82; P < .001) and 1.71-fold in association with the combination of phonation and reflux events., Conclusions: Antecedent phonation and reflux increased the rate of cough events in patients with idiopathic chronic cough. Reflux events were more strongly associated with increased rate of coughing. Our findings support the concept that airway hypersensitivity is a cause of chronic cough, and that the vocal folds may be an effector in chronic cough ClinicalTrials.gov number: NCT01263626., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Asthma is a chronic disease of the lung associated with airway hyperresponsiveness (AHR), airway obstruction and airway remodeling. Airway remodeling involves differentiation of airway epithelial cells into myofibroblasts via epithelial-mesenchymal transition (EMT) to intensify the degree of subepithelial fibrosis. EMT involves loss in E-cadherin with an increase in mesenchymal markers, including vimentin and N-cadherin. There is growing evidence that vitamin D has immunomodulatory and anti-inflammatory properties. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we examined the contribution of vitamin D on the AHR, airway inflammation and expression of EMT markers in the airways of mice sensitized and challenged with a combination of clinically relevant allergens, house dust mite, ragweed, and Alternaria (HRA). Female Balb/c mice were fed with vitamin D-sufficient (2000 IU/kg) or vitamin D-supplemented (10,000 IU/kg) diet followed by sensitization with HRA. The density of inflammatory cells in the bronchoalveolar lavage fluid (BALF), lung histology, and expression of EMT markers by immunofluorescence were examined. Vitamin D-supplementation decreased AHR, airway inflammation in the BALF and the features of airway remodeling compared to vitamin D-sufficiency in HRA-sensitized and -challenged mice. This was accompanied with increased expression of E-cadherin and decreased vimentin and N-cadherin expression in the airways. These results indicate that vitamin D may be a beneficial adjunct in the treatment regime in allergic asthma.

Background: Sputum is a key diagnostic sample for those with chronic chest conditions including chronic and allergic aspergillus-related disease, but often not obtained in clinic. The objective of this study was to evaluate physiotherapeutic interventions to obtain sputum from those not able to spontaneously produce and the subsequent microbiological result., Methods: Sputum samples were collected by physiotherapists from patients attending routine outpatient clinics managing their aspergillus-related diseases who were unable to spontaneously produce. Active Cycle of Breathing Techniques (ACBT) technique was applied first, for 10 min, followed by hypertonic saline induction using a Pari LC plus or Pari Sprint nebuliser, if necessary and deemed safe to do so. Samples processed in the laboratory using standard microbiological techniques for bacterial and fungal culture with the addition of Aspergillus real-time PCR., Results: Samples were procured from 353 of 364 (97%) patients, 231 (65%) by ACBT and 119 (34%) with administration of hypertonic saline. Three of 125 (2.4%) patients had significant bronchospasm during sputum induction. Sixteen patients' sputum tested positive for Aspergillus culture, contrasting with 82 whose Aspergillus PCR was positive, 59 with a strong signal. PCR improved detection of Aspergillus by 350%. Sputum from 124 (34%) patients cultured other potentially pathogenic organisms which justified specific therapy., Conclusions: Physiotherapeutic interventions safely and effectively procured sputum from patients unable to spontaneously produce. The method for sputum induction was well-tolerated and time-efficient, with important microbiological results.

It is known that asthma is a heterogeneous entity whose manifestations vary with age. Our objective was to examine changes in the manifestation of asthma and asthma-related traits in childhood by defining empirically derived childhood asthma phenotypes and examining their transitions over time.To define the phenotypes we used data on respiratory symptoms, healthcare utilisation, medications, spirometry, airway hyperresponsiveness (AHR), exhaled nitric oxide concentration and atopy from a birth cohort recruited on the basis of having a first-degree relative with asthma. Data were acquired at ages 1.5-11.5 years and analysed using latent transition analysis.In a study population of 370 participants, we classified subjects into four phenotypes: 1) nonatopic, few symptoms (prevalence range from 1.5 to 5 years: 52-60%), 2) atopic, few symptoms (3-21%), 3) nonatopic, asthma and rhinitis symptoms (13-35%), and 4) atopic, asthma and rhinitis symptoms (2-14%) in early childhood; and 1) nonatopic, no respiratory disease (prevalence range from 8 to 11.5 years: 41-46%), 2) atopic, no respiratory disease (23-33%), 3) nonatopic, asthma symptoms, no AHR or airway inflammation (8-12%) and 4) atopic asthma (19%) in mid-childhood. Transitioning between phenotypes was common in early childhood, but less common in later childhood.This analysis represents the first attempt to incorporate longitudinal patterns of several manifestations of asthma into a single model to simultaneously define phenotypes and examine their transitions over time. It provides quantitative support for the view that asthma is a heterogeneous entity, and that some children with wheeze and other respiratory symptoms in early life progress to asthma in mid-childhood, while others become asymptomatic., (Copyright ©ERS 2016.)

Purpose: The purpose of this study was to determine the prevalence of lymphoid hyperplasia in the lower gastrointestinal tract and its role in patients undergoing colonoscopic examinations, particularly focusing on any allergic predisposition., Methods: A database search performed at the Department of Gastroenterology at Onomichi Municipal Hospital identified seven patients with lymphoid hyperplasia in the large intestine (i.e., cecum, colon, and/or rectum). Data regarding the endoscopic, biological, and pathological examinations performed and the allergic histories for each patient were retrospectively reviewed from the clinical records., Results: Median age of the patients (four males, three females) was 50 years. Lymphoid hyperplasia was seen in the cecum (n = 5), ascending colon (n = 2), and transverse colon (n = 1). Six patients (85.7%) had one of the allergic airway diseases: allergic rhinoconjunctivitis for pollen (n = 3), bronchial asthma (n = 1), infantile asthma (n = 1), or allergic bronchitis (n = 1). Drug allergy (n = 3) and urticaria (n = 2) were also found. All seven patients had one or more allergic diseases; however, none had a history of food allergy. Blood tests for allergens revealed that six patients (85.7%) had positive reactions to inherent allergens, whereas only one patient had a positive reaction to food allergens., Conclusions: Our results indicate that lymphoid hyperplasia in the large intestine may be associated with allergic airway diseases rather than with food allergies; thus, its presence may be useful to detect patients with underlying airway hyperreactivity.

Cystic fibrosis transmembrane conductance regulator deficient mouse models develop phenotypes of relevance to clinical cystic fibrosis (CF) including airway hyperresponsiveness, small intestinal bacterial overgrowth and an altered intestinal microbiome. As dysbiosis of the intestinal microbiota has been recognized as an important contributor to many systemic diseases, herein we investigated whether altering the intestinal microbiome of BALB/c Cftr(tm1UNC) mice and wild-type littermates, through treatment with the antibiotic streptomycin, affects the CF lung, intestinal and bone disease. We demonstrate that streptomycin treatment reduced the intestinal bacterial overgrowth in Cftr(tm1UNC) mice and altered the intestinal microbiome similarly in Cftr(tm1UNC) and wild-type mice, principally by affecting Lactobacillus levels. Airway hyperresponsiveness of Cftr(tm1UNC) mice was ameliorated with streptomycin, and correlated with Lactobacillus abundance in the intestine. Additionally, streptomycin treated Cftr(tm1UNC) and wild-type mice displayed an increased percentage of pulmonary and mesenteric lymph node Th17, CD8 + IL-17+ and CD8 + IFNγ+ lymphocytes, while the CF-specific increase in respiratory IL-17 producing γδ T cells was decreased in streptomycin treated Cftr(tm1UNC) mice. Bone disease and intestinal phenotypes were not affected by streptomycin treatment. The airway hyperresponsiveness and lymphocyte profile of BALB/c Cftr(tm1UNC) mice were affected by streptomycin treatment, revealing a potential intestinal microbiome influence on lung response in BALB/c Cftr(tm1UNC) mice.

Nasal hyperresponsiveness (NHR) is a characteristic feature of allergic rhinitis (AR); however, the pathogenesis of NHR is not fully understood. In this study, during the establishment of an experimental AR model using ovalbumin-immunized and -challenged mice, augmentation of the sneezing reaction in response to nonspecific proteins as well as a chemical stimulant was detected. Whether NHR is independent of mast cells and eosinophils was determined by using mast cell- and eosinophil-deficient mice. NHR was suppressed by treatment with anti-CD4 antibody, suggesting the pivotal contribution of CD4+ T cells. Furthermore, antigen challenge to mice to which in vitro-differentiated Th1, Th2, and Th17 cells but not naïve CD4+ T cells had been adoptively transferred led to the development of equivalent NHR. Since antigen-specific IgE and IgG were not produced in these mice and since antigen-specific IgE-transgenic mice did not develop NHR even upon antigen challenge, humoral immunity would be dispensable for NHR. CD4+ T cells play a crucial role in the pathogenesis of AR via induction of NHR, independent of IgE-, mast cell-, and eosinophil-mediated responses.

Introduction: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however., Methods: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays., Results: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR., Conclusion: MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.

Objective: Asthma and abdominal aortic aneurysms (AAA) both involve inflammation. Patients with asthma have an increased risk of developing AAA or experiencing aortic rupture. This study tests the development of one disease on the progression of the other., Approach and Results: Ovalbumin sensitization and challenge in mice led to the development of allergic lung inflammation (ALI). Subcutaneous infusion of angiotensin II into mice produced AAA. Simultaneous production of ALI in AAA mice doubled abdominal aortic diameter and increased macrophage and mast cell content, arterial media smooth muscle cell loss, cell proliferation, and angiogenesis in AAA lesions. ALI also increased plasma IgE, reduced plasma interleukin-5, and increased bronchioalveolar total inflammatory cell and eosinophil accumulation. Intraperitoneal administration of an anti-IgE antibody suppressed AAA lesion formation and reduced lesion inflammation, plasma IgE, and bronchioalveolar inflammation. Pre-establishment of ALI also increased AAA lesion size, lesion accumulation of macrophages and mast cells, media smooth muscle cell loss, and plasma IgE, reduced plasma interleukin-5, interleukin-13, and transforming growth factor-β, and increased bronchioalveolar inflammation. Consequent production of ALI also doubled lesion size of pre-established AAA and increased lesion mast cell and T-cell accumulation, media smooth muscle cell loss, lesion cell proliferation and apoptosis, plasma IgE, and bronchioalveolar inflammation. In periaortic CaCl2 injury-induced AAA in mice, production of ALI also increased AAA formation, lesion inflammation, plasma IgE, and bronchioalveolar inflammatory cell accumulation., Conclusions: This study suggests a pathological link between airway allergic disease and AAA. Production of one disease aggravates the progression of the other., (© 2015 American Heart Association, Inc.)

Surfactant protein D (SP-D) is a pulmonary collectin important in lung immunity. SP-D-deficient mice (Sftpd(-/-)) are reported to be susceptible to ovalbumin (OVA)- and fungal allergen-induced pulmonary inflammation, while treatment with exogenous SP-D has therapeutic effects in such disease models. β-Glucans are a diverse group of polysaccharides previously suggested to serve as fungal ligands for SP-D. We set out to investigate if SP-D could interact with 1,3-β-glucan and attenuate allergic pulmonary inflammation in the presence of 1,3-β-glucan. Allergic airway disease was induced in Sftpd(-/-) and Sftpd(+/+) mice by OVA sensitization and subsequent challenge with OVA, 1,3-β-glucan, or OVA/1,3-β-glucan together. Mice in the combined treatment group were further treated with a high dose of recombinant fragment of human SP-D (rfhSP-D). We demonstrated direct interaction between SP-D and 1,3-β-glucan. OVA-induced mucous cell metaplasia was increased in Sftpd(-/-) mice, supporting previously reported protective effects of endogenous SP-D in allergy. OVA-induced parenchymal CCL11 levels and eosinophilic infiltration in bronchoalveolar lavage were unaffected by 1,3-β-glucan, but were reversed with rfhSP-D treatment. 1,3-β-Glucan treatment did, however, induce pulmonary neutrophilic infiltration and increased TNF-α levels in bronchoalveolar lavage, independently of OVA-induced allergy. This infiltration was also reversed by treatment with rfhSP-D. 1,3-β-Glucan reduced OVA-induced mucous cell metaplasia, T helper 2 cytokines, and IFN-γ production. rfhSP-D treatment further reduced mucous metaplasia and T helper 2 cytokine secretion to background levels. In summary, rfhSP-D treatment resulted in attenuation of both allergic inflammation and 1,3-β-glucan-mediated neutrophilic inflammation. Our data suggest that treatment with high-dose SP-D protects from mold-induced exacerbations of allergic asthma., (Copyright © 2015 the American Physiological Society.)