Reduce Airway Inflammation Research Articles

Erdosteine reduces inflammation and time to first exacerbation postdischarge in hospitalized patients with AECOPD.

PurposeMucolytics can improve disease outcome in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The objectives of this study were to investigate the effects of erdosteine (ER), a mucolytic agent with antioxidant activity, on systemic inflammation, symptoms, recurrence of exacerbation, and time to first exacerbation postdischarge in hospitalized patients with AECOPD.Patients and methodsPatients admitted to hospital with AECOPD were randomized to receive either ER 900 mg daily (n=20) or a matching control (n=20). Treatment was continued for 10 days until discharge. Patients also received standard treatment with steroids, nebulized bronchodilators, and antibiotics as appropriate. Serum C-reactive protein levels, lung function, and breathlessness–cough–sputum scale were measured on hospital admission and thereafter at days 10 and 30 posttreatment. Recurrence of AECOPD-requiring antibiotics and/or oral steroids and time to first exacerbation in the 2 months (days 30 and 60) postdischarge were also assessed.ResultsMean serum C-reactive protein levels were lower in both groups at days 10 and 30, compared with those on admission, with significantly lower levels in the ER group at day 10. Improvements in symptom score and forced expiratory volume in 1 second were greater in the ER than the control group, which reached statistical significance on day 10. ER was associated with a 39% lower risk of exacerbations and a significant delay in time to first exacerbation (log-rank test P=0.009 and 0.075 at days 30 and 60, respectively) compared with controls.ConclusionResults confirm that the addition of ER (900 mg/d) to standard treatment improves outcomes in patients with AECOPD. ER significantly reduced airway inflammation, improved the symptoms of AECOPD, and prolonged time to first exacerbation. The authors suggest ER could be most beneficial in patients with recurring, prolonged, and/or severe exacerbations of COPD.

Clinical study of low molecular weight heparin combined isoproterenol inhalation in treatment of children with severe bronchial pneumonia

Objective To explore clinical efficacy of low molecular weight heparin combined isoproterenol inhalation in treatment of children with severe bronchial pneumonia. Methods 110 patients from Jan 2013 to Apr 2014 were collected and randomly divided into treatment group (57 cases)and control group(53 cases), control group was given anti infection, hormone, expectorant, oxygen and other symptomatic treatment, besides, inhaled with isoprenaline, bid, based on which treatment group was inhalaled with low molecular weight heparin sodium injection, qd, arterial blood gas indexes were compared between 2 groups after 72 h treatment, and clinical efficacy were compared after 5 d treatment. Results After 72 h treatment, two groups of children with pulmonary function, arterial blood gas index and airway inflammatory improved obviously; treatment group with PaO2 and PaO2/FiO2 were significantly higher than control group, while PaCO2, CRP were significantly lower than control group, the differences of all above indexes were statistically significant (P 0.05). During inhalation, two groups with incidences of temporary heart rate rise (10.5% vs.13.2)had no significant difference (χ2=0.189 P=0.663 ). Conclusion Based on conventional treatment for children with severe pneumonia, low molecular weight heparin combined with isoproterenol inhalation can improve pulmonary ventilation function, reduce airway inflammation, and improve clinical efficacy to a certain extent. Key words: Bronchial pneumonia; Low molecular weight heparin; Isoproterenol; Inhalation; Pulmonary function

Effect of lactobacillus salivarius on asthma Balb/c mouse in IL-4, IFN-γ and IgE of serum and lung tissue homogenates

Objective To invstigate the effect of Lactobacillus salivarius on asthma Balb/ c mouse in IgE, IL-4 and IFN-γ of serum and lung tissue homogenates. Methods Thirty female Balb/c mice weighing 16-18 g (4 weeks old), SPF grade, were randomly divided into three groups: normal control group (N), asthma group(A), asthma combined Lactobacillus salivarius group (AH). Acute asthma model was established by ovalbumin challenge method, mice were observed in behavioral changes, non-invasive method for the determination of airway responsiveness in mice, the changes in airway inflammation and the number changes of tracheal cilia were observed by pathological HE staining and the electron microscope.Respectively, the levels of IgE and IL-4/IFN-γ in the serum and lung tissue homogenate were measured by ELISA. Results five~ten min after 4%OVA saline solution atomization excitation mice in A group appeared obvious restlessness, head and facial itching, scratching, shortness of breath, perioral cyanosis with abdominal breathing, sneezing, stooping, forelimbs shrinkage, urine and feces incontinence and other asthma acute phase performances, The above reaction alleviated in AH group compared to A group; Pathology of HE staining in asthma group showed the thickening bronchial wall, narrow lumen, peribronchial and perivascular infiltration with a large number of eosinophil-based inflammatory cells, lumen with many inflammatory secretions, Pathological changes in lung tissue of mice in AH group significantly alleviated compared with asthma group; Under the electron microscope, the number of cilia in A group significantly decreased compared with N group, while AH group significantly increased compared with A group; Expression level of IgE, IL-4 in the serum and lung homogenate of A group was significantly higher than that of N group(P<0.05), the level of IFN-γ expression was significantly lower than N group(P<0.05), however the expression level of IgE, IL-4 in AH group significantly decreased compared with A group(P<0.05), and IFN-γ expression level elevated compared with A group(P<0.05). Conclusion Lavage with Lactobacillus salivarius before sensitization could alleviate clinical symptoms of asthmatic mice, partially correct Th1/Th2 imbalance as well as reduce airway inflammation. Key words: Lactobacillus salivarius; Asthma; IgE; IL-4; IFN-γ; Mouse

Inhibition of airway inflammation and remodeling by sitagliptin in murine chronic asthma

In this study the role of sitagliptin, dipeptidyl peptidase inhibitor, DPP-4, and dexamethasone in ameliorating inflammation and remodeling of chronic asthma in a mouse model were investigated. Mice sensitized to ovalbumin were chronically challenged with aerosolized antigen for 3days a week continued for 8weeks. During this period animals were treated with sitagliptin or dexamethasone daily. Assessment of inflammatory cell, oxidative markers, total nitrate/nitrite (NOx), interleukin (IL)-13, transforming growth factor-beta1 (TGF-β1) in bronchoalveolar lavage (BAL) and/or lung tissue were done. Also histopathological and immuno-histochemical analysis for lung was carried out. Compared with vehicle alone, treatment with sitagliptin or dexamethasone significantly reduced accumulation of eosinophils and chronic inflammatory cells, subepithelial collagenization, and thickening of the airway epithelium. Also both drug reduced goblet cell hyperplasia, oxidative stress, TGF-β1, IL-13 and epithelial cytoplasmic immunoreactivity for nuclear factor κ-B (NFκ-B). These data indicate that sitagliptin like dexamethasone may play a beneficial role reducing airway inflammation and remodeling in chronic murine model of asthma.

Clinical asthma phenotypes in the real world: opportunities and challenges.

Key PointsAsthma is a heterogeneous syndrome ranging from mild disease with barely noticeable symptoms to very severe disease with constant symptoms that may greatly hinder patients’ quality of life.The aim of asthma treatment is control of asthma and the prevention of risk of exacerbations and fixed airflow limitation.Asthma management must be individualised; tailored not only to the severity of the disease but importantly, to the phenotypic characteristics of the patient and modified according to response to treatment.Educational AimsTo inform readers about the current understanding on the treatment of asthma.To highlight the usefulness of phenotypes in treating asthmatic patients, especially those with severe disease.To introduce the issues of severe asthma management and future planning.Asthma is a common, chronic and heterogeneous syndrome, affecting people of all ages, all races and both sexes. It may range from mild disease with barely noticeable symptoms, to very severe disease with constant symptoms that greatly hinder the life of the patient. Guidelines issued by various medical societies provide guidance on how to diagnose and manage asthmatic patients. It is now increasingly recognised that asthma management must be individualised, tailored not only to the severity of the disease but to the phenotypic characteristics of each patient. The aim of asthma treatment is control of asthma and the prevention of risk of exacerbations and fixed airflow limitation. Asthma control can be easily assessed clinically through simple screening tools such as the use of validated questionnaires and spirometry. The use of inflammatory biomarkers can be an alternative approach that, however, requires more time and resources. Asthma treatment involves the use of controllers, mainly inhaled corticosteroids and long-acting β2-agonists, and relievers, mainly rapid-acting β2-agonists. Controller medications reduce airway inflammation, lead to better symptom control and reduce the risk of future exacerbations. Reliever (rescue) medications alleviate symptoms and prevent exercise-induced bronchoconstriction. Treatment must be based on a “stepwise approach” in order to achieve good control of symptoms and to minimise future risks of exacerbations. That is, less treatment for mild disease, more treatment for severe, uncontrolled disease. Once good asthma control has been achieved and maintained, treatment should be stepped down. In severe asthmatics, phenotypic characterisation becomes more clinically useful and add-on treatment such as anti-immunoglobulin E monoclonal antibodies may be required. Despite our better understanding of asthma, there are still patients who will not respond to treatment and remain symptomatic. Dissemination of guidelines and national plans allowing early diagnosis of asthma as well as access to specialised primary and secondary care for asthmatic patients, personalised treatment and continuity of care may lead to excellence in care and controlled asthma for the majority of patients. Education of the patient in asthma is also very important, as in every chronic disease, as the patients live with the disease every day while they visit a healthcare professional a few times a year. Future planning for new treatments should focus on the needs of such severe asthma patients.

Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness.

The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE-/-) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE-/- mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE-/- mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.

The influence of Lactobacillus salivarius on IgE, eosinophil cationic protein and transforming growth factor-β in serum and lung tissue homogenates of asthmic Balb/c mouse

Objective To explore the influence of Lactobacillus salivarius on IgE, eosinophil cationic protein(ECP) and transforming growth factor(TGF)-β of serum and lung tissue homogenates of asthmic Balb/c mouse. Methods Thirty female Balb/c mice weighing 16-18 g(4 weeks old), SPF grade, were randomly divided into three groups: normal control group(group A), asthma group(group B), asthma combined Lactobacillus salivarius group(group C). Acute asthma model was established applying ovalbumin, behavioral changes were observed in mice, the changes in airway inflammation and the number changes of tracheal cilia were observed by pathological HE staining and the electron microscope respectively.The levels of IgE, ECP and TGF-β in the serum and lung tissue homogenate were measured by ELISA method. Results (1)The mice in group B presented obvious restlessness, head and facial itching, scratching, shortness of breath, perioral cyanosis with abdominal breathing, sneezing, stooping, forelimbs shrinkage, urine and feces incontinence and other asthma acute phase performances in 5-10 minuts after 4% ovalbumin saline solution atomization excitation, the above reaction alleviated in group C compared to group B. (2) Pathology of HE staining in group B showed the thickening bronchial wall, narrow lumen, peribronchial and perivascular infiltration with a large number of eosinophil-based inflammatory cells, lumen with many inflammatory secretions, pathological changes in lung tissue of mice in group C significantly alleviated compared with group B. Under the electron microscope, the number of cilia in group B significantly decreased compared with group A, while group C significantly increased compared with group B. (3) Expression levels of serum IgE and ECP in group C were significantly lower than those in group B[(0.86±0.14) μg/ml vs.(1.30±0.12) μg/ml; (2.30±0.15) ng/ml vs.(3.41±0.15) ng/ml, P<0.05, respectively]. The contents of lung tissue homogenate IgE[(0.97±0.06) μg/ml] and ECP[(5.88±0.13) ng/ml] in group C significantly decreased, respectively, compared with the IgE[(1.13±0.05) μg/ml] and ECP[(8.08±0.15) ng/ml] in group B(P<0.05). The levels of serum TGF-β[(0.17±0.01) μg/ml] and lung tissue homogenates TGF-β[(0.18±0.01) μg/ml] in group C were higher than the serum TGF-β[(0.13±0.01) μg/ml] and lung tissue homogenates TGF-β[(0.15±0.01) μg/ml] in group B, respectively, the differences were statistically significant(P<0.05). Conclusion Lavage with Lactobacillus salivarius before sensitization could alleviate clinical symptoms of asthmatic mice, as well as reduce airway inflammation in some degree, TGF-β may be involved in the mechanism of Lactobacillus salivarius playing a protective role. Key words: Lactobacillus salivarius; Asthma; IgE; ECP; TGF-β

Deficiency of FHL2 attenuates airway inflammation in mice and genetic variation associates with human bronchial hyper-responsiveness.

Asthma is an inflammatory disease that involves airway hyper-responsiveness and mucus hypersecretion. The LIM-only protein FHL2 is a crucial modulator of multiple signal transduction pathways and functions as a scaffold in specific protein-protein interactions. We sought to investigate the role of FHL2 in airway inflammation. Allergic airway inflammation was induced in WT and FHL2-knock out (FHL2-KO) mice with ovalbumin (OVA). Lung tissue, bronchoalveolar lavage fluid (BALF) and draining lymph node cells were analysed for inflammation. FHL2 loss and gain of function studies were performed in lung epithelial cells. FHL2-deficient mice challenged with OVA show significantly reduced airway inflammation as evidenced by reduced infiltration of inflammatory cells including eosinophils, dendritic cells, B cells and T cells. Furthermore, mucus production was decreased in FHL2-KO mice. In BALF, the levels of IL-5, IL-13, eotaxin-1 and eotaxin-2 were significantly lower in FHL2-KO mice. In addition, draining lymph node cells from FHL2-KO mice show reduced levels of IL-5 and IL-13. Consistent with this, OVA-specific serum IgG and IgE levels were reduced in FHL2-KO mice. We also found that phosphorylation of ERK1/2 is markedly attenuated in FHL2-KO lung. Knock-down of FHL2 in human lung epithelial cells resulted in a striking decrease in ERK1/2 phosphorylation and mRNA levels of inflammatory cytokines and MUC5AC, whereas FHL2 overexpression exhibited opposite effects. Finally, the SNP rs4851765 shows an association with the severity of bronchial hyper-responsiveness. These results highlight functional involvement of FHL2 in airway inflammation and identify FHL2 as a novel gene associated with asthma severity in human.

Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation.

Complement is implicated in asthma pathogenesis, but its mechanism of action in this disease remains incompletely understood. In this study, we investigated the role of properdin (P), a positive alternative pathway complement regulator, in allergen-induced airway inflammation. Allergen challenge stimulated P release into the airways of asthmatic patients, and P levels positively correlated with proinflammatory cytokines in human bronchoalveolar lavage (BAL). High levels of P were also detected in the BAL of OVA-sensitized and challenged but not naive mice. Compared with wild-type (WT) mice, P-deficient (P(-/-)) mice had markedly reduced total and eosinophil cell counts in BAL and significantly attenuated airway hyperresponsiveness to methacholine. Ab blocking of P at both sensitization and challenge phases or at challenge phase alone, but not at sensitization phase alone, reduced airway inflammation. Conversely, intranasal reconstitution of P to P(-/-) mice at the challenge phase restored airway inflammation to wild-type levels. Notably, C3a levels in the BAL of OVA-challenged P(-/-) mice were significantly lower than in wild-type mice, and intranasal coadministration of an anti-C3a mAb with P to P(-/-) mice prevented restoration of airway inflammation. These results show that P plays a key role in allergen-induced airway inflammation and represents a potential therapeutic target for human asthma.

Small molecule inhibitor of neutrophil elastase reduces emphysema in mice with cystic fibrosis-like lung disease

Background: Increased neutrophil elastase (NE) activity in bronchoalveolar lavage (BAL) fluid in newborns with cystic fibrosis (CF) has been shown to correlate with lung damage in juvenile age. Mice with airway- specific overexpression of the epithelial Na+ channel (βENaC-Tg) phenocopy CF lung disease with mucus obstruction, chronic inflammation and emphysema. Genetic deletion of NE in βENaC-Tg mice reduced airway inflammation and emphysema, indicating that NE may serve as a therapeutic target.

Antigen-specific cytotoxic T lymphocytes target airway CD103+ and CD11b+ dendritic cells to suppress allergic inflammation.

Allergic airway inflammation is driven by the recognition of inhaled allergen by T helper type 2 (Th2) cells in the airway and lung. Allergen-specific cytotoxic T lymphocytes (CTLs) can strongly reduce airway inflammation, however, the mechanism of their inhibitory activity is not fully defined. We used mouse models to show that allergen-specific CTLs reduced early cytokine production by Th2 cells in lung, and their subsequent accumulation and production of interleukin (IL)-4 and IL-13. In addition, treatment with specific CTLs also increased the proportion of caspase(+) dendritic cells (DCs) in mediastinal lymph node (MLN), and decreased the numbers of CD103(+) and CD11b(+) DCs in the lung. This decrease required expression of the cytotoxic mediator perforin in CTLs and of the appropriate MHC-antigen ligand on DCs, suggesting that direct CTL-DC contact was necessary. Lastly, lung imaging experiments revealed that in airway-challenged mice XCR1-GFP(+) DCs, corresponding to the CD103(+) DC subset, and XCR1-GFP(-) CD11c(+) cells, which include CD11b(+) DCs and alveolar macrophages, both clustered in the areas surrounding the small airways and were closely associated with allergen-specific CTLs. Thus, allergen-specific CTLs reduce allergic airway inflammation by depleting CD103(+) and CD11b(+) DC populations in the lung, and may constitute a mechanism through which allergic immune responses are regulated.

Efficacy of erdosteine 900 versus 600 mg/day in reducing oxidative stress in patients with COPD exacerbations: Results of a double blind, placebo-controlled trial

BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with increased airway and systemic inflammation. There is evidence that erdosteine accelerates recovery from AECOPD by reducing airway inflammation. AimTo investigate the dose-dependent antioxidant/anti-inflammatory activity of erdosteine in COPD patients. MethodsIn this single-centre, double blind, double dummy study, patients with mild-to-moderate COPD (GOLD stage II–III), were randomised to receive either placebo or two dosages of oral erdosteine (300 mg tid or 300 mg bid + 1 capsule of indistinguishable placebo) for 28 days in addition to their standard treatment. Primary variables were plasma reactive oxygen species (ROS) and 8-isoprostane levels, while secondary variable was lung function (FEV1; FEV1/FVC; FEV1 short-term reversibility), all assessed in baseline; every two weeks during the study, and one week after the end of the study. ResultsBaseline demographic characteristics, plasma ROS and 8-isoprostane levels and lung function were not significantly different in the 24 eligible patients (14 males, aged 38–75 years). At 2 weeks, there was a dose-dependent decrease in ROS in the erdosteine groups. By week 4 there were significant differences in ROS levels compared to baseline between patients receiving 900 mg/day (p < 0.003) and those receiving 600 mg/day (p < 0.04). This effect continued in the follow-up week (p < 0.021). Erdosteine also lowered 8-isoprostane plasma levels after 4 weeks (p < 0.01), and this effect lasted over the post-treatment week. Moreover, % FEV1 reversibility after salbutamol 400 mcg obtained after a 4 -week treatment of erdosteine 900 mg/day was significantly higher than that obtained after 600 mg/day (p < 0.01). Erdosteine was well tolerated and no treatment-related adverse event was reported. ConclusionsResults confirm the antioxidant dose- and time-dependent activity of erdosteine, and support the utility of including erdosteine it in the therapeutic strategy for the prevention and treatment of oxidative stress-induced inflammation, which frequently leads to AECOPD occurrence.

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

Effects of simvastatin on airway inflammation and airway mucus hypersecretion in rats with chronic obstructive pulmonary disease

To explore the preventive and therapeutic effects of simvastatin on rats with chronic obstructive pulmonary disease (COPD) and examine the mechanism of airway inflammation and airway mucus hypersecretion. The rat model of COPD was established by cigarette smoking and an intratracheal injection of lipopolysaccharide (LPS). A total of 18 male Sprague-Dawley rats were randomly divided into control, COPD and simvastatin groups (n=6 each). The control and COPD groups received normal saline once daily via intragastric administration (i.g.) while the simvastatin group had simvastatin (0.5 g/L) 1 ml/100 g once daily via i.g. Pulmonary function was tested and pathological changes in bronchus and lung were observed. The bronchoalveolar lavage fluid (BALF) levels of interleukin-8 (IL-8), interleukin-17 (IL-17) and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assay (ELISA). The protein expressions of intercellular adhesion molecule 1 (ICAM-1), nuclear factor κB (NF-κB), mucin 5AC (MUC5AC) and Toll-like receptor 4 (TLR4) in rat airway were detected by immunohistochemical staining. The mRNA and protein expressions of TLR4 and MUC5AC in bronchi and lung tissue were detected by fluorescent real time quantitative polymerase chain reaction (RT-PCR) and Western blot. The changes of bronchi and lung tissues in COPD group were consistent with typical pathological manifestations of COPD. As compared with the COPD group, the degree of pulmonary pathological damage and the decline of pulmonary function in the simvastatin group were significantly lessened, but still remarkable as compared with the control group. The BALF levels of IL-8, IL-17 and TNF-α in the smvastatin group [(484.4 ± 11.1), (78.9 ± 2.0), (192.7 ± 2.0) ng/L] were significantly lower than those in the COPD group [(605 ± 48.7), (89.9 ± 6.9), (212.6 ± 10.7) ng/L], but still higher than those in the control group [(341.2 ± 21.4), (56.0 ± 2.9), (127.5 ± 9.0) ng/L respectively] (all P <0.01). Compared with COPD group, the expression levels of ICAM-1, NF-κB, MUC5AC and TLR4 protein were significantly lower in the simvastatin group, but still higher than the control group (all P <0.01). Furthermore, the expression levels of mRNA and protein of MUC5AC and TLR4 were significantly lower in the simvastatin group than those in the COPD group (all P <0.05). In COPD model rats, simvastatin can decrease the levels of IL-8, IL-17 and TNF-α in BALF and inhibit the expression levels of ICAM-1, NF-κB, MUC5AC and TLR4 protein in airway and lung tissue. Thus it plays preventive and therapeutic roles by reducing airway inflammation and airway mucus hypersecretion.

Four-year follow-up in children with moderate/severe uncontrolled asthma after withdrawal of a 1-year omalizumab treatment.

Allergic asthma, which is the most frequent asthma phenotype, is mainly a chronic inflammatory disease characterized by elevated serum IgE levels and specific-IgE against common allergens. A significant group of asthmatic children have uncontrolled moderate/severe symptoms despite the use of medium/high doses of inhaled corticosteroids (ICS) in combination with another controller. Asthma guidelines suggest omalizumab as an add-on therapy in these children and recent evidence has shown the efficacy and safety of this mAb against IgE. Asthma cannot be cured and current available treatments are unable to modify the natural course of the disease. Recent studies have shown positive effects of omalizumab in reducing airway inflammation and remodelling. Herein, a 4-year follow-up of a group of children with moderate/severe uncontrolled asthma taking part in a randomized double blind placebo control with omalizumab is shown. After discontinuation of anti-IgE, children were followed up for 4 years. During the first 3 years of follow-up, they were completely free of asthma symptoms without any need of ICS or rescue medication. The new evidence published and the clinical observation described herein generate the hypothesis that treatment with omalizumab could potentially modify the natural course of asthma. However, further studies are needed.

The effect of selective antagonist of H4 receptor JNJ7777120 on nasal symptoms, cough, airway reactivity and inflammation in guinea pigs

The efficacy of H4R antagonist JNJ7777120 on nasal symptoms, cough, airway resistance (Raw), inflammatory cell count in bronchoalveolar lavage (BAL) and blood in ovalbumin (OVA) induced allergic rhinitis (AR) was studied in guinea pigs. Animals (n=8) were sensitized by i.p. OVA and were repeatedly challenged with nasal OVA to induce rhinitis, seven animals were not sensitized. Animals were pre-treated with JNJ7777120 2.5 and 5mg/kg i.p. 30min prior OVA. Cough was induced by inhalation of citric acid, Raw was measured in vivo by Pennock's method as baseline, during AR and after JNJ7777120 treatment. Leucocyte count in BAL and blood was analyzed. JNJ7777120 (5mg/kg) significantly suppressed nasal symptoms and the number of coughs. This compound significantly inhibited airway reactivity to histamine, but not methacholine. Pre-treatment with JNJ7777120 5mg/kg did not influence significantly the leucocyte count in BAL and blood except for a significant decrease in monocyte count in blood compared to the control group (p<0.05). We conclude that the antitussive action of JNJ7777120 is peripheral. The primary effect of the compound is anti-inflammatory, and the suppression of cough is a consequence of reduced airway inflammation.

Haemophilus influenzae responds to glucocorticoids used in asthma therapy by modulation of biofilm formation and antibiotic resistance.

Glucocorticosteroids are used as a main treatment to reduce airway inflammation in people with asthma who suffer from neutrophilic airway inflammation, a condition frequently associated with Haemophilus influenzae colonization. Here we show that glucocorticosteroids have a direct influence on the behavior of H. influenzae that may account for associated difficulties with therapy. Using a mouse model of infection, we show that corticosteroid treatment promotes H. influenzae persistence. Transcriptomic analysis of bacteria either isolated from infected mouse airway or grown in laboratory medium identified a number of genes encoding regulatory factors whose expression responded to the presence of glucocorticosteroids. Importantly, a number of these corticosteroid-responsive genes also showed elevated expression in H. influenzae within sputum from asthma patients undergoing steroid treatment. Addition of corticosteroid to H. influenzae led to alteration in biofilm formation and enhanced resistance to azithromycin, and promoted azithromycin resistance in an animal model of respiratory infection. Taken together, these data strongly suggest that H. influenzae can respond directly to corticosteroid treatment in the airway potentially influencing biofilm formation, persistence and the efficacy of antibiotic treatment.

Combination effects of Gumiganghwal-tang water extract and montelukast on airway inflammation in human bronchial epithelial cells

Purpose: Gumiganghwal-tang (known as Kumi-Kyokatsuto in Japanese) is well known traditional herbal prescription, which consists of 12 different herbs; Osterici Radix, Saposhnikoviae Radix, Cnidii Rhizoma, Angelicae Dahuricae Radix, Atractylodis Rhizoma, Scutellariae Radix, Rehmanniae Radix, Asari Radix et Rhizoma, Glycyrrhizae Radix et Rhizoma, Zingiberis Rhizoma Recens, Zizyphi Fructus, and Allii Fistulosi Bulbus. Gumiganghwal-tang has been commonly used in various disease including common cold, pain, and inflammatory diseases in Korea. Montelukast has been used as an effective therapeutic agent for prevention and treatment of allergic rhinitis or asthma. The objective of this study is to find out the combination effect on interaction of Gumiganghwaltang water extract (GGTW) and montelukast using human bronchial epithelial, BEAS-2B cells. Methods:Anti-inflammation effects were selected to study the effects on IL-4/TNF-induced inflammatory response in BEAS2B cells. Cell supernatants and mRNA were collected for cellular inflammatory mediators determined via enzymelinked immunosorbent assay, gelatin zymography, and polymerase chain reaction. Results: After treatment of IL-4/TNF, the production of eotaxin, regulated on activation of normal T-cell-expressedandsecreted (RANTES), matrix metalloproteinases-9 (MMP9), and vascular cell adhesion molecule (VCAM)-1 expression were increased. However, each of GGTW and montelukast was significantly inhibit the production of eotaxin, RANTES, MMP-9, andVCAM-1 expression.Moreover, drug combinations (co-treatment ofGGTWwithmontelukast)weremore effective than each treatment, although the difference was not significant. Conclusion: Taken together, these findings suggest that GGTW combined with montelukast may be useful to reduce airway inflammation, which may explain its beneficial effect for the regulation of inflammatory disease. Contact: Woo-Young Jeon, ssamggun85@kiom.re.kr

IL-17RA Signaling in Airway Inflammation and Bronchial Hyperreactivity in Allergic Asthma.

Asthma is a heterogeneous disease characterized by airway inflammation and hyperreactivity. IL-17 receptor A (IL-17RA) is a shared receptor subunit required for activity of IL-17 family cytokines, including IL-17A and IL-25. IL-17A and IL-25 induce different proinflammatory responses, and concentrations are elevated in subjects with asthma. However, the individual contributions of IL-17A and IL-25 to disease pathogenesis are unclear. We explored proinflammatory activities of the IL-17 pathway in models of pulmonary inflammation and assessed its effects on contractility of human bronchial airway smooth muscle. In two mouse models, IL-17RA, IL-17RB, or IL-25 blockade reduced airway inflammation and airway hyperreactivity. Individually, IL-17A and IL-25 enhanced contractility of human bronchial smooth muscle induced by methacholine or carbachol. IL-17A had more pronounced effects on methacholine-induced contractility in bronchial rings from donors with asthma compared with donors without asthma. Blocking the IL-17 pathway via IL-17RA may be a useful therapy for some patients with asthma by reducing pulmonary inflammation and airway hyperreactivity.

Ligation of TLR7 on CD19(+) CD1d(hi) B cells suppresses allergic lung inflammation via regulatory T cells.

Bcells have been described as having the capacity to regulate cellular immune responses and suppress inflammatory processes. One such regulatory B-cell population is defined as IL-10-producing CD19(+) CD1d(hi) cells. Previous work has identified an expansion of these cells in mice infected with the helminth, Schistosoma mansoni. Here, microarray analysis of CD19(+) CD1d(hi) Bcells from mice infected with S. mansoni demonstrated significantly increased Tlr7 expression, while CD19(+) CD1d(hi) Bcells from uninfected mice also demonstrated elevated Tlr7 expression. Using IL-10 reporter, Il10(-/-) and Tlr7(-/-) mice, we formally demonstrate that TLR7 ligation of CD19(+) CD1d(hi) Bcells increases their capacity to produce IL-10. In a mouse model of allergic lung inflammation, the adoptive transfer of TLR7-elicited CD19(+) CD1d(hi) Bcells reduced airway inflammation and associated airway hyperresponsiveness. Using DEREG mice to deplete FoxP3(+) T regulatory cells in allergen-sensitized mice, we show that that TLR7-elicited CD19(+) CD1d(hi) Bcells suppress airway hyperresponsiveness via a T regulatory cell dependent mechanism. These studies identify that TLR7 stimulation leads to the expansion of IL-10-producing CD19(+) CD1d(hi) Bcells, which can suppress allergic lung inflammation via T regulatory cells.