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Objective: Immunoglobulin A (IgA) is suggested to have pathogenic effects in respiratory inflammatory diseases, including asthma. We aimed to analyze the relationship between serum IgA, and clinical indicators and biomarkers of asthma. Methods: This study was a post hoc analysis of the NHOM Asthma Study. In this study, serum IgA was measured using serum samples stored. We determined an association between the serum IgA level and clinical variables and biomarkers using multivariate linear regression and analyzed the differences in clinical indices between IgA high- and IgA low-asthma. Results: In this study, 572 patients with asthma were included in the final analysis. Lower percentage forced expiratory volume in the first second (%FEV 1 ), higher serum eotaxin levels, lower serum ST2 levels, and higher serum MIP-1β levels, were independently and significantly associated with higher serum IgA levels among asthma patients by multivariate linear regression analysis (%FEV 1 , 95% confidence interval [CI], -8.18- -0.613, p  < 0.05; eotaxin, 95% CI, 8.95-46.69, p  < 0.001; ST2, 95% CI, -73.71- -7.37, p  < 0.05; and MIP-1β, 95% CI, 1.47-18.71, p  < 0.05). Furthermore, IgA high-asthma (serum IgA ≥ 238 mg/dL, n  = 270) and IgA low-asthma (serum IgA < 238 mg/dL, n  = 302) were compared separately. %FEV 1 was significantly lower, the percentage of atopy was higher, and serum MIP-1β level was higher in IgA high-asthma. Conclusions: This study suggests that serum IgA may be involved in the worsening of asthma outcomes, as assessed by %FEV 1 and enhanced inflammation via elevated serum MIP-1β.

Objective Dupilumab, a monoclonal antibody specific for the human interleukin (IL)-4 receptor α, is used to treat severe asthma, especially in patients with elevated blood eosinophil counts and fractional exhaled nitric oxide (FeNO). The therapeutic response to dupilumab is highly variable. In this study, we explored new serum biomarkers to accurately predict the effect of dupilumab and examine the effect of dupilumab based on changes in the clinical parameters and cytokine levels. Methods Seventeen patients with severe asthma treated with dupilumab were enrolled. Responders, defined as those with a >0.5-point decrease in the Asthma Control Questionnaire (ACQ) score after 6 months of treatment, were included. Results There were 10 responders and 7 non-responders. Serum type 2 cytokines were equivalent between responders and non-responders; the baseline serum IL-18 level was significantly lower in responders than in non-responders (responders, 194.9±51.0 pg/mL; non-responders, 323.4±122.7 pg/mL, p=0.013). The cut-off value of IL-18 at 230.5 pg/mL could be used to distinguish non-responders from responders (sensitivity 71.4, specificity 80.0, p=0.032). Conclusion A low baseline serum IL-18 level may be a useful predictor of an unfavorable response to dupilumab in terms of the ACQ-6.

Background: Obesity leads to an increase in the incidence and severity of asthma. Adipokines, such as leptin, secreted by adipocytes induce systemic inflammation, causing airway inflammation. We previously reported that leptin activates both inflammatory and structural cells, including lung fibroblasts. However, little is known about the differential leptin expression and responsiveness to leptin in asthmatic individuals and healthy controls (HC). In this study, we investigated the expression and origin of leptin in asthmatic airways. We also compared the effect of leptin on asthmatic and HC fibroblasts., Methods: Lung specimens from asthmatic and non-asthmatic patients were analyzed by immunohistochemical staining using anti-leptin and anti-CD163 antibodies. Leptin mRNA and protein levels in human monocytes were detected by real-time PCR and western blotting and ELISA, respectively. We used flow cytometry to analyze asthmatic and HC lung fibroblasts for leptin receptor (Ob-R) expression. Further, we determined cytokine levels using cytometric bead array and ELISA and intracellular phosphorylation of specific signaling molecules using western blotting., Results: Asthma specimens displayed accumulation of leptin-positive inflammatory cells, which were also positive for CD163, a high-affinity scavenger receptor expressed by monocytes and macrophages. Leptin expression was observed at both transcript and protein levels in human blood-derived monocytes. No significant differences were observed between asthmatic and HC lung fibroblasts in Ob-R expression, cytokine production, and intracellular phosphorylation of p38 mitogen-activated protein kinase., Conclusions: Our findings reveal similar responsiveness of control and asthmatic fibroblasts to leptin. However, the accumulation of inflammatory leptin-producing monocytes in the airway may contribute to the pathogenesis of asthma., Competing Interests: Conflict of Interest MS received honoraria from AstraZeneca and research funding from AstraZeneca and GlaxoSmithKline. SKW received research funding from Sanofi. The other authors have no conflict of interest., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objective: Benralizumab, a humanized monoclonal antibody against human IL-5 receptor alpha, is effective in treating eosinophilic severe asthma. However, patients' response to benralizumab varies widely. In this study, we aimed to identify a new serum biomarker to accurately predict benralizumab response., Methods: Seventeen benralizumab-treated patients with severe eosinophilic asthma were enrolled. Blood samples were collected; pulmonary function tests were performed and questionnaires were disseminated at baseline and after 1, 2, 4, and 6 months of treatment. Blood cytokine levels were measured. Response was defined as an elevation in forced expiratory volume in 1 s of at least 10.4% from baseline after 4 months of treatment., Results: There were nine respondents and eight non-respondents. The non-responders showed significantly higher baseline serum interferon-γ; interleukin (IL)-4, -5, -6, -7, and -12p70; IL-17/IL-17A; IL-17E/IL-25; IL-18/IL-1F4; chemokine (C-C motif) ligand (CCL)3/macrophage inflammatory protein (MIP)-1α; CCL4/MIP-1β; CCL11/eotaxin; matrix metalloproteinase-12; tumor necrosis factor-α, and thymic stromal lymphopoietin levels. After benralizumab administration, the serum CCL3/MIP-1α and CCL11/eotaxin levels significantly and persistently increased in the responders (CCL3/MIP-1α, responders: 144.5 ± 37.9 pg/ml (baseline) vs. 210.3 ± 59.4 pg/ml (4 months), p  = 0.009; non-responders: 270.8 ± 139.8 pg/ml (baseline) vs. 299.5 ± 159.9 pg/ml (4 months), p  = 0.33; CCL11/eotaxin, responders: 167.9 ± 62.6 pg/ml (baseline) vs. 326.7 ± 134.4 pg/ml (4 months), p  = 0.038; non-responders: 420.9 ± 323.1 pg/ml (baseline) vs. 502.1 ± 406.0 pg/ml (4 months), p  = 0.30)., Conclusion: Low baseline serum inflammatory cytokine levels may be useful in predicting a good benralizumab response.Supplemental data for this article is available online at at www.tandfonline.com/ijas .

Background: Myeloid differentiation protein-2 (MD-2) is a lipopolysaccharide-binding protein involved in lipopolysaccharide signalling via Toll-like receptor 4 (TLR4). TLR4 plays an essential role in HDM-mediated allergic airway inflammation. Moreover, MD-2 is structurally similar to Der f 2, a major allergen from house dust mite (HDM)., Objectives: We aimed to clarify the role of MD-2 in the pathogenesis of HDM-mediated allergic airway inflammation., Methods: Wild-type (WT), TLR4 knockout and MD-2 knockout mice were subjected to intranasal instillation of HDM extract, and asthmatic features were evaluated. We also evaluated gene sets regulated by MD-2 in HDM-treated airway epithelial cells and examined the function of dendritic cells from lymph nodes and from lungs., Results: Aggravated allergic airway inflammation with increased airway hyperresponsiveness was observed in MD-2 knockout mice compared with WT and TLR4 knockout mice. Global gene expression analysis revealed an MD-2 regulated proinflammatory response and reconstituted TLR4 signalling in airway epithelial cells. The ability of dendritic cells to evoke an allergic immune response was enhanced in MD-2 knockout mice., Conclusions & Clinical Relevance: MD-2 plays a protective role in HDM-induced airway allergy with the proinflammatory regulation of airway epithelial cells and dendritic cells. MD-2 may serve as a therapeutic target in the treatment of asthma., (© 2021 John Wiley & Sons Ltd.)

Inhaler devices play an important role in the management of obstructive lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap. Some of these patients show suboptimal inhaler techniques; however, time for inhaler instruction by pharmacists is limited in daily clinical practice. Therefore, sufficient education regarding inhaler device handling should be provided within a limited time frame. The current study aimed to investigate the instruction methods provided by community pharmacists and their influence on inhaler device handling techniques in outpatient clinical care settings. We retrospectively collected the data of outpatients with obstructive lung diseases who were referred to our hospital and who underwent inhalation technique assessments conducted by community pharmacists. The prevalence of handling errors, clinical characteristics of patients, and instruction methods were analyzed. In total, 138 patients (170 devices) were included in this study. Approximately 70.0% of patients received verbal explanations combined with leaflets about inhaler instructions. In a device-based analysis, 63 (37.1%) of 170 devices had at least one technical error and 18 (10.6%) of the devices had critical errors. Patients without critical errors received practical demonstration instructions from pharmacists combined with leaflets and verbal explanations more frequently than those with critical errors (22.8 vs. 0%, p < 0.01). This study revealed that patients with obstructive lung diseases commonly present with inhaler device handling errors and critical errors were observed with non-negligible frequency in daily practice in Japan. Combined instruction with leaflet, verbal explanation, and pharmacist demonstration may be effective in improving proper inhaler treatment.

Background: Type 2 innate lymphoid cells (ILC2s) are one of the sources of IL-5 and IL-13 in allergic airway inflammation. Innate immune receptors such as Toll-like receptors (TLRs) expressed on epithelial cells could contribute to ILC2 activation through IL-33 production, but a direct effect of TLRs on ILC2s remains to be elucidated., Objectives: We hypothesized that TLRs can directly activate lung ILC2s and participate in the pathogenesis of asthma., Methods: After intranasal administration of IL-33 to wild-type (WT), TLR2KO and TLR4KO female mice, ILC2s were isolated from harvested lungs. ILC2s were incubated with IL-2 and TLR stimulants (pam3csk4 (PAM), house dust mite extract (HDM)). In some experiments, TLR2 or dectin-1 signalling inhibitors were used. As an in vivo model, the mice were treated with IL-33 and rested until lung recruitment of eosinophils regressed. Then they were treated intranasally with PAM + HDM or vehicle and analysed., Results: In vitro stimulation of isolated ILC2s showed that PAM could induce IL-13 and IL-5 production, and HDM had a synergistic effect on this stimulation. Both effects were dependent on TLR2 and NF-κB signalling. PAM + HDM stimulation of WT mice led to increased ILC2s, airway hyperresponsiveness and increased levels of both neutrophils and eosinophils in bronchoalveolar lavage fluid. These observations were dependent on TLR2., Conclusions & Clinical Relevance: TLR2 can directly activate lung ILC2s, an effect that is augmented by HDM. Asthmatic characteristics mediated through the TLR2 pathway were evident in the in vivo mice model. These data implicate a new pathway of ILC2 activation in the pathogenesis of asthma., (© 2019 John Wiley & Sons Ltd.)

House dust mites (HDMs) are a common source of allergens that trigger both allergen-specific and innate immune responses in humans. Here, we examined the effect of allergen concentration and the involvement of Toll-like receptor 4 (TLR4) in the process of sensitization to house dust mite allergens in an HDM extract-induced asthma mouse model.　Intranasal administration of HDM extract induced an immunoglobulin E response and eosinophilic inflammation in a dose-dependent manner from 2.5 to 30 μg/dose. In TLR4-knockout mice, the infiltration of eosinophils and neutrophils into the lung was decreased compared with that in wild-type mice in the early phase of inflammation (total of three doses). However, in the late phase of inflammation (total of seven doses), eosinophil infiltration was significantly greater in TLR4-knockout mice than in wild-type mice. This suggests that the roles of TLR4 signaling are different between the early phase and the later phase of HDM allergen-induced inflammation. Thus, innate immune response through TLR4 regulated the response to HDM allergens, and the regulation was altered during the phase of inflammation., (© 2018 The Foundation for the Scandinavian Journal of Immunology.)

Background: Asthma is a chronic airway inflammatory disease characterized by airway remodeling, in which the bronchial smooth muscle (BSM) cells play an important role. Periostin, a biomarker that reflects Th2-driven inflammatory diseases such as asthma, may play an important role in the asthmatic airway. Although periostin is mainly produced in airway epithelial cells and fibroblasts after interleukin (IL)-13 stimulation, whether BSM cells produce periostin remains unclear. Therefore, we investigated periostin production in BSM cells and the mechanisms involved., Methods: Human BSM cells were cultured, and the effect of IL-13 stimulation on periostin production was evaluated using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). We evaluated the phosphorylation of signal transducer and activator of transcription factor 6 (STAT6), extracellular signal-regulated kinase (ERK)1/2, and Akt after IL-13 stimulation. Furthermore, using ELISA, we evaluated the influence of several phosphorylation inhibitors on periostin production., Results: Periostin mRNA expression increased in a dose- and time-dependent manner after IL-13 stimulation; periostin production was induced 24 and 48 h after stimulation. IL-13 stimulation induced the phosphorylation of STAT6, ERK1/2, and Akt. IL-13-induced periostin production was attenuated by inhibiting STAT6 phosphorylation and strongly suppressed by inhibiting mitogen-activated protein kinase kinase 1/2 phosphorylation or phosphatidylinositol 3-kinase (PI3K) phosphorylation., Conclusions: BSM cells produced periostin after IL-13 stimulation, via the JAK/STAT6, ERK1/2, and PI3K/Akt pathways. Understanding the mechanism of periostin production in BSM cells may help to clarify asthma pathogenesis., (© 2018 S. Karger AG, Basel.)

Background: Asthma exacerbation may require a visit to the emergency room as well as hospitalization and can occasionally be fatal. However, there is limited information about the prognostic factors for asthma exacerbation requiring hospitalization, and no methods are available to predict an inpatient's prognosis. We investigated the clinical features and factors affecting in-hospital mortality of patients with asthma exacerbation and generated a nomogram to predict in-hospital death using a national inpatient database in Japan., Methods: We retrospectively collected data concerning hospitalization of adult patients with asthma exacerbation between July 2010 and March 2013 using the Japanese Diagnosis Procedure Combination database. We recorded patient characteristics and performed Cox proportional hazards regression analysis to assess the factors associated with all-cause in-hospital mortality. Then, we constructed a nomogram to predict in-hospital death., Results: A total of 19,684 patients with asthma exacerbation were identified; their mean age was 58.8 years (standard deviation, 19.7 years) and median length of hospital stay was 8 days (interquartile range, 5-12 days). Among study patients, 118 died in the hospital (0.6%). Factors associated with higher in-hospital mortality included older age, male sex, reduced level of consciousness, pneumonia, and heart failure. A nomogram was generated to predict the in-hospital death based on the existence of seven variables at admission. The nomogram allowed us to estimate the probability of in-hospital death, and the calibration plot based on these results was well fitted to predict the in-hospital prognosis., Conclusion: Our nomogram allows physicians to predict individual risk of in-hospital death in patients with asthma exacerbation.

Background and Objective: There is increasing recognition of asthma-COPD overlap syndrome (ACOS), which shares some features of both asthma and COPD; however, the prevalence and characteristics of ACOS are not well understood. The aim of this study was to investigate the prevalence of ACOS among patients with COPD and its characteristics using a stepwise approach as stated in the recent report of the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD)., Methods: This multicenter, cross-sectional, observational study enrolled outpatients who were receiving medical treatment for COPD. Clinical data, including spirometry results, were retrieved from medical records. For symptom assessment, patients were asked to complete the Clinical COPD questionnaire and the modified British Medical Research Council questionnaire., Results: Of the 1,008 patients analyzed, 167 (16.6%) had syndromic features of ACOS. Of the total number of patients, 93 and 42 (9.2% and 4.2%) also had a predefined clinical variability of ≥12%/≥200 mL and ≥12%/≥400 mL in forced expiratory volume in 1 second (FEV 1 ), respectively, and therefore were identified as having ACOS. Conversely, the number of patients who had either syndromic or spirometric feature of ACOS was 595 (59.0%, ≥12%/≥200 mL FEV 1 clinical variability), and 328 patients (32.5%, ≥12%/≥400 mL FEV 1 clinical variability) had both the features. Patients identified as having ACOS were of significantly younger age, had a shorter duration of COPD, lower number of pack-years, better lung function, milder dyspnea symptoms, and higher peripheral blood eosinophil values compared with patients with COPD alone. The rate of exacerbations in the previous year was not significantly different between the ACOS and COPD groups., Conclusion: Using a stepwise approach, as stated in the GINA/GOLD report, the proportions of patients identified as having ACOS were found to be 9.2% and 4.2% (depending on the FEV 1 variability cutoff used) among the 1,008 outpatients medically treated for COPD in a real-life clinical setting., Competing Interests: Disclosure Hiromasa Inoue has received research funding and lecture fees from AstraZeneca K.K. Satoshi Morita has received personal fees from AstraZeneca K.K. Atsushi Yoshida and Tatsunori Jinnai are employees of AstraZeneca K.K. Masakazu Ichinose has received research funding from AstraZeneca K.K. The authors report no other conflicts of interest in this work.

Chronic inflammatory airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease, are common respiratory disorders worldwide. Exacerbations of these diseases are frequent and worsen patients' respiratory condition and overall health. However, the mechanisms of exacerbation have not been fully elucidated. Recently, it was reported that interleukin (IL)-17A might play an important role in neutrophilic inflammation, which is characteristic of such exacerbations, through increased production of neutrophil chemoattractants. Therefore, we hypothesized that IL-17A was involved in the pathogenesis of acute exacerbation, due to viral infection in chronic inflammatory airway diseases. In this study, we assessed chemokine production by bronchial epithelial cells and investigated the underlying mechanisms. Comprehensive chemokine analysis showed that, compared with poly(I:C) alone, co-stimulation of BEAS-2B cells with IL-17A and poly(I:C) strongly induced production of such neutrophil chemoattractants as CXC chemokine ligand (CXCL)8, growth-related oncogene (GRO), and CXCL1. Co-stimulation synergistically induced CXCL8 and CXCL1 mRNA and protein production by BEAS-2B cells and normal human bronchial epithelial cells. Poly(I:C) induced chemokine expression by BEAS-2B cells mainly via Toll-like receptor 3/TIR-domain-containing adapter-inducing interferon-β-mediated signals. The co-stimulation with IL-17A and poly(I:C) markedly activated the p38 and extracellular-signal-regulated kinase 1/2 pathway, compared with poly(I:C), although there was little change in nuclear factor-κB translocation into the nucleus or the transcriptional activities of nuclear factor-κB and activator protein 1. IL-17A promoted stabilization of CXCL8 mRNA in BEAS-2B cells treated with poly(I:C). In conclusion, IL-17A appears to be involved in the pathogenesis of chronic inflammatory airway disease exacerbation, due to viral infection by promoting release of neutrophil chemoattractants from bronchial epithelial cells.

Background and Objective: Obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), have airflow limitation associated with chronic inflammation. Using a national inpatient database in Japan, we aimed to evaluate factors affecting in-hospital mortality in patients with asthma, COPD or asthma-COPD overlap (ACO)., Methods: We retrospectively collected data for inpatients (age >40 years) with exacerbation of COPD and/or asthma in 1073 hospitals across Japan between July 2010 and May 2013. We performed multivariable logistic regression analysis to examine the association of various factors with all-cause in-hospital mortality, including diagnosis of ACO, asthma alone and COPD alone., Results: Of 30 405 eligible patients, in-hospital mortality in patients with ACO, asthma alone and COPD alone was 2.3%, 1.2% and 9.7%, respectively. COPD patients had a significantly higher mortality than ACO patients (odds ratio 1.96; 95% confidence interval: 1.38-2.79); patients with asthma alone showed lower mortality (0.70; 0.50-0.97). Higher mortality was also significantly associated with older age, male gender, lower body mass index, more severe dyspnoea, lower level of consciousness, worse activities of daily life and higher daily dose of corticosteroids., Conclusion: Asthma alone was associated with lower mortality, but COPD alone was associated with higher mortality than ACO., (© 2015 Asian Pacific Society of Respirology.)

Asthma-related mortality has been decreasing due to inhaled corticosteroid use, but severe asthma remains a major clinical problem. One characteristic of severe asthma is resistance to steroid therapy, which is related to neutrophilic inflammation. Recently, the tumor necrosis factor superfamily member (TNFSF) 14/LIGHT has been recognized as a key mediator in severe asthmatic airway inflammation. However, the profiles and intracellular mechanisms of cytokine/chemokine production induced in cells by LIGHT are poorly understood. We aimed to elucidate the molecular mechanism of LIGHT-induced cytokine/chemokine production by bronchial epithelial cells. Human bronchial epithelial cells express lymphotoxin β receptor (LTβR), but not herpesvirus entry mediator, which are receptors for LIGHT. LIGHT induced various cytokines/chemokines, such as interleukin (IL)-6, oncostatin M, monocyte chemotactic protein-1, growth-regulated protein α and IL-8. Specific siRNA for LTβR attenuated IL-6 and IL-8 production by BEAS-2B and normal human bronchial epithelial cells. LIGHT activated intracellular signaling, such as mitogen-activated protein kinase and nuclear factor-κB (NF-κB) signaling. LIGHT also induced luciferase activity of NF-κB response element, but not of activator protein-1 or serum response element. Specific inhibitors of phosphorylation of extracellular signal-regulated kinase (Erk) and that of inhibitor κB attenuated IL-8 production, suggesting that LIGHT-LTβR signaling induces IL-8 production via the Erk and NF-κB pathways. LIGHT, via LTβR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells.

To advance the control of airway epithelial cell function and asthma, we investigated the effects of a new curcumin derivative, CNB001, which possesses improved pharmacological properties. Normal human bronchial epithelial (NHBE) cells were stimulated with synthetic double-stranded RNA, Poly(I:C). CNB001 significantly suppressed IL-6, TNF-α, and GM-CSF production by NHBE cells, and did so more effectively than did curcumin or dexamethasone (DEX). CNB001 significantly inhibited the decrease of E-cadherin mRNA expression and increase of vimentin mRNA expression observed in NHBE cells induced by a combination of TGF-β1 and TNF-α, which are markers of airway remodeling. In NHBE cells stimulated by TGF-β1, CNB001 significantly downregulated the level of active serine peptidase inhibitor clade E member (SERPINE) 1, which is also reported to be related to airway remodeling. Whereas DEX alone significantly increased the active SERPINE1 level, the combination of DEX and CNB001 significantly suppressed active SERPINE1. In addition, CNB001 significantly suppressed neutrophil infiltration, IL-6, TNF-α, IL-13 and active SERPINE1 production in bronchoalveolar lavage fluid of the murine asthma model, which was not observed in the case of DEX. In conclusion, the curcumin derivative, CNB001, is a promising candidate to treat asthma associated with neutrophilic airway inflammation and remodeling., (Copyright © 2012 Elsevier Inc. All rights reserved.)

House dust mite (HDM), the most common allergen, activate both the IgE-associated and innate immune responses. To clarify the process of sensitization, we investigated the role of the CCL21, CCL19, and CCR7 axis in a mouse model of HDM-induced allergic asthma. HDM inhalation without systemic immunization resulted in a HDM-specific IgE response. CCR7-knockout (CCR7KO) mice exhibited greater airway inflammation and IgE responses compared to wild-type mice. We examined FoxP3 expression in these mice to clarify the contribution of regulatory cells to the responses. FoxP3 expression was higher in the lungs but not in the lymph nodes of CCR7KO mice compared to wild-type mice. In CCR7KO mice, FoxP3-positive cells were found in lung, but we observed higher release of IL-13, IL-5, TGF-β, IL-17, and HMGB1 in bronchoalveolar lavage fluid. We demonstrate here that immuno-regulation through CCR7 expression in T cells plays a role in HDM-specific sensitization in the airway., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Whereas acetylcholine (ACh) acts as a bronchoconstrictor and stimulator of mucus secretion from bronchial epithelium, it acts via alpha7 nicotinic Ach receptors (nAChRs) on macrophages in the airways to exert anti-inflammatory effects by reducing synthesis of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). Moreover, the effects of ACh are modified by secreted ly-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of alpha7 nAChR signaling. Our aim was to explore the roles played by SLURP-1 in the pathophysiology of asthma by assessing SLURP-1 expression in the OVA-sensitized murine asthma model and in cultured human bronchial epithelial cells. Using real-time PCR we found that expression of SLURP-1 mRNA is down-regulated in the lungs of asthmatic model mice, as compared to healthy mice. In addition, immunohistochemical studies confirmed the diminished expression of SLURP-1 in the bronchioles of asthmatic mice, and showed it was due to extensive metaplasia of mucus-secreting cells and the concomitant loss of ciliated epithelial cells. Expression of SLURP-1 mRNA and protein was also significantly down-regulated in human epithelial cells stimulated with the pro-inflammatory cytokine interleukin-13 (IL-13), which is related to asthmatic condition. Thus SLURP-1 appears to be down-regulated in both an animal model of asthma and human epithelial cells treated with an inflammatory cytokine related to asthma. Those findings suggest that diminished expression of SLURP-1 in asthma attenuates its negative regulation of airway inflammation, and that perhaps changes in SLURP-1 expression could serve as a marker of airway damage in asthma., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Adrenomedullin (ADM), a newly identified vasodilating peptide, is reported to be expressed in lungs and have a bronchodilating effect. We hypothesized whether ADM could be involved in the pathogenesis of bronchial asthma. We examined the role of ADM in airway responsiveness using heterozygous ADM-deficient mice (AM+/-) and their littermate control (AM+/+). Here, we show that airway responsiveness is enhanced in ADM mutant mice after sensitization and challenge with ovalbumin (OVA). The immunoreactive ADM level in the lung tissue after methacholine challenge was significantly greater in the wild-type mice than that in the mutant. However, the impairment of ADM gene function did not affect immunoglobulins (OVA-specific IgE and IgG1), T helper 1 and 2 cytokines, and leukotrenes. Thus the conventional mechanism of allergen-induced airway responsiveness is not relevant to this model. Furthermore, morphometric analysis revealed that eosinophilia and airway hypersecretion were similarly found in both the OVA-treated ADM mutant mice and the OVA-treated wild-type mice. On the other hand, the area of the airway smooth muscle layer of the OVA-treated mutant mice was significantly greater than that of the OVA-treated wild-type mice. These results suggest that ADM gene disruption may be associated with airway smooth muscle hyperplasia as well as enhanced airway hyperresponsiveness. ADM mutant mice might provide novel insights to study the pathophysiological role of ADM in vivo.

Lipid mediators play an important role in modulating inflammatory responses. Platelet-activating factor (PAF) is a potent proinflammatory phospholipid with eosinophil chemotactic activity in vitro and in vivo. We show in this study that mice deficient in PAF receptor exhibited significantly reduced airway hyperresponsiveness to muscarinic cholinergic stimulation in an asthma model. However, PAF receptor-deficient mice developed an eosinophilic inflammatory response at a comparable level to that of wild-type mice. These results indicate an important role for PAF receptor, downstream of the eosinophilic inflammatory cascade, in regulating airway responsiveness after sensitization and aeroallergen challenge.

We conducted a longitudinal investigation with the QOL questionnaire (revised version 2001) before and after the 4-week-administration of a leukotriene receptor antagonist pranlukast. A significant improvement in the < 4 yrs group was observed at week 1, and that in > or = 4 yrs group at week 2. Under these conditions, the overall QOL score, physical domains and mental domains, significantly improved in both the < 4 yrs group and the > or = 4 yrs group. Overall, a slight correlation was observed between ratio changes in QOL scores and differences in symptom scores. However, no correlation was found in part of patients, suggesting that the QOL questionnaire allows measurement of mental changes in the patients themselves and their parents or caregivers for therapeutic effects which cannot be determined with ordinary physical findings only. In "event present" group, a significant difference in physical and mental domains was revealed by the comparison of QOL scores before and after administration. And furthermore in "event absence" group, the p-value for physical domain and mental domain was 0.0505 and 0.0912 in the < 4 yrs group, respectively, 0.0101 and 0.0446 in the > or = 4 yrs group, respectively. The above results led us to consider the QOL questionnaire (revised version 2001) useful for routine medical care. Furthermore, pranlukast was considered useful for improvement not only of physical symptoms of bronchial asthma but also of the patient's QOL, although the placebo effects in this open trial must be considered.

We have recently demonstrated that tissue resistance increases during the early response to antigen challenge in sensitized Brown-Norway rats. The purpose of the present study was to investigate in vitro the dynamic tissue response to antigen challenge and the involvement of the mediators, i.e., serotonin (5HT) and leukotriene D4 (LTD4). In addition, we questioned whether strips from sensitized rats responded differently to nonspecific challenge compared with those of unsensitized controls. We sensitized Brown-Norway rats with ovalbumin and performed experiments using strips of subpleural parenchyma. Tissue strips were challenged with ovalbumin in the bath; in some experiments the tissues were exposed to methysergide (10(-6) M), a 5HT antagonist, or MK-571 (10(-6) M), a LTD4 receptor antagonist, or both, prior to challenge. At the end of the experiment all tissues were exposed to carbacholine (10(-3) M). Oscillation mechanics of tissue strips were studied and values of resistance (R), elastance (E), and hysteresivity (eta) were obtained. During ovalbumin challenge in sensitized tissues, R, E, and eta increased significantly (% change in R, 12.1 +/- 2.1%; % change in E, 3.8 +/- 1.3%; % change in eta, 9.3 +/- 2.8%). Both methysergide and MK-571 reduced the increase in R (3.0 +/- 0.6 and 3.2 +/- 0.8%, respectively, p < 0.05 vs. ovalbumin). There was no difference between sensitized and unsensitized strips in the response to carbacholine challenge. These data suggest that the oscillatory behaviour of tissue strips from sensitized rats is altered after ovalbumin challenge. The mechanism of that response is mediated by both 5HT and LTD4.

Airway inflammation is involved in the pathogenesis of bronchial asthma. Intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen-1 alpha (LFA-1 alpha) and has been shown to be required for leukocyte migration into inflamed area. The purpose of this report was to investigate the role of ICAM-1/LFA-1 alpha pathway in a rat model of extrinsic asthma using monoclonal antibodies (mAbs). We chose to study ovalbumin (OA)-sensitized Brown-Norway rats, an animal model in which there is a high prevalence of both early (ER) and late responses (LR) after antigen challenge. We measured tracheal and alveolar pressure using alveolar capsules in open-chested, mechanically ventilated animals to calculate resistance of lung (RL), tissue (Rti), and airway (Raw). In the OA group, both ER (RL, Rti, Raw = 263 +/- 16, 235 +/- 10, 309 +/- 38% baseline) and LR (RL, Rti, Raw = 265 +/- 26, 238 +/- 13, 316 +/- 55% baseline) were observed. The administration of mAbs to ICAM-1 and LFA-1 alpha significantly attenuated the ER (RL, Rti, Raw = 146 +/- 9, 141 +/- 11, 156 +/- 8% baseline) and LR (RL, Rti, Raw = 128 +/- 8, 124 +/- 5, 137 +/- 1% baseline), indicating that both airway and lung tissues were involved in this mechanism. The current observations suggest that ICAM-1/LFA-1 alpha pathway is involved in both the early and late responses in a rat model of allergic asthma. The antagonism of ICAM-1 and LFA-1 alpha may provide a potential therapeutic approach to the early and late responses of bronchial asthma.