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Background: HDM SLIT is one of the disease-modifying treatment for allergic asthma, and has demonstrated efficacy in clinical trials. Dupilumab, blocks IL-4 and IL-13 signaling, key drivers of type 2 inflammation, and is approved for patients with uncontrolled, moderate-to-severe asthma. The aim of this study was to evaluate outcomes after HDM SLIT initiation in asthma with rhinitis not optimally controlled with dupilumab in a real-world setting., Methods: At baseline and 48 weeks after treatment, asthma control questionnaire (ACQ)-5, asthma quality of life questionnaire (AQLQ) and rhinoconjunctivitis quality of life questionnaire (RQLQ) were assessed. Spirometry, type 2 inflammatory biomarkers and quantitative computed tomographic parameters of airway remodeling were also collected., Results: Of 47 patients received HDM SLIT and 41 completed the study. Combined HDM SLIT and dupilumab improved ACQ-5 (p < 0.05), AQLQ (p < 0.05), RQLQ (p < 0.05), and increased lung function and reduced FeNO (p < 0.05) and airway percentage wall area, and wall thickness (each, p < 0.05). The change in ACQ-5 and AQLQ score correlated with both changes in FeNO and FEV 1 percent predicted. Multiple regression analysis showed that the change in FEV 1 percent predicted was independent factor for improvement of AQLQ (r 2  = 0.510, p = 0.012). Based on ROC analysis for predicting SLIT responders, the baseline area under the curves in serum HDM specific-IgE, total IgE and FEV 1 percent predicted were high (>0.8)., Conclusions: These results support the benefits of adding HDM SLIT to pharmacotherapy plus dupilumab in uncontrolled asthma with rhinitis., (Copyright © 2022 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: House dust mite (HDM) sublingual immunotherapy (SLIT) has demonstrated efficacy in clinical trials of patients with asthma. Airway inflammation is a characteristic of respiratory allergy, but its relationship to SLIT remains unclear., Objective: We evaluate the association between clinical outcomes with pulmonary function and biomarkers in before and after HDM SLIT (UMIN Number 000022390)., Methods: One hundred twelve patients with asthma sensitized to HDM were randomized to add-on 6 standardized quality (SQ)-HDM SLIT to pharmacotherapy or pharmacotherapy alone for 48 weeks. At baseline and end of study, biomarkers, blood eosinophils, serum IgE, serum periostin, fractional exhaled nitric oxide (FeNO), and spirometry and clinical symptoms were measured. Association between biomarkers and an increase in FEV 1 of 120 mL or greater were analysed., Results: Sublingual immunotherapy (SLIT) demonstrated a significant reduction of serum periostin (P < .001), FeNO (P < .01), and increase in HDM-specific IgE (P < .05), FEV 1 (P < .001) and improvement of clinical symptom scores, when compared to pharmacotherapy. The change in FEV 1 correlated with the changes in serum periostin (r = .696, P < .001) and the changes in FeNO (r = .682, P < .001). The independent predictor of improvement in airflow limitation was changed in serum periostin (r 2  = .753, P = .013) and FeNO (P = .038). Based on cut-off values derived by receiver operating characteristic analysis (periostin 30.9 ng/mL, FeNO 28.0 ppb), patients were distinguished responders from non-responders, but with no predictive value for blood eosinophils or total IgE. The proportion of patients with both high periostin and FeNO levels was significantly higher in responder than in non-responder (P = .026)., Conclusions and Clinical Relevance: Adding HDM SLIT to pharmacotherapy resulted in reduced serum periostin and FeNO, and improved pulmonary function. Serum periostin and FeNO may be useful biomarkers for prediction of SLIT., (© 2020 John Wiley & Sons Ltd.)

Background: The efficacy of the standardized quality (SQ) house dust mite (HDM) sublingual immunotherapy (SLIT) has been demonstrated for respiratory allergic disease. However, the effects of SLIT on inflammation and structural changes of the airways are still unknown., Objective: The aim of this study was to assess the effects of the 6 SQ-HDM SLIT on airway inflammation and airway geometry in allergic asthma and rhinitis., Methods: One hundred two asthmatic patients with rhinitis sensitized to HDM were randomized to receive either SLIT plus pharmacotherapy or standard pharmacotherapy alone, for 48 weeks. Fractional exhaled nitric oxide (FeNO), pulmonary function, quantitative computed tomography, and clinical symptoms were performed at baseline and end of the study., Results: Compared with pharmacotherapy, SLIT demonstrated a significant reduction of FeNO (P < .01), airway wall area/body surface area (WA/BSA, P < .001), wall thickness (T/√BSA, P < .001), percentage wall area (WA/Ao, P < .01), increase in luminal area (Ai/BSA, P < .05), improvement of airflow limitation (P < .001), and clinical symptom scores (P < .05). The change in forced expiratory volume in 1 second (FEV 1 ) was correlated with both changes in FeNO and airway dimensions. Multiple regression analysis showed that the change in FeNO was independently associated with an increase in FEV 1 in the SLIT group (r 2  = 0.623, P = .037)., Conclusions: Adding 6 SQ-HDM SLIT to standard asthma therapy provides a significant improvement in symptoms and pulmonary function compared with pharmacotherapy. Improvement of airflow limitation with SLIT was associated with the decrease in eosinophilic airway inflammation., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective : Asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS) alone or with ICS plus a long-acting β 2 -agonist (LABA). The recommended alternative is the addition of either montelukast or tiotropium. The aim of this study was to compare the effects of montelukast and tiotropium on airway inflammation and remodeling in persistent asthma. Methods : Eighty-seven patients with asthma were treated with budesonide and formoterol (640/18 μg); then, the patients were randomly allocated to three groups to receive oral montelukast (10 mg/day), inhaled tiotropium (5 μg/day), or no add-on to the maintenance therapy for 48 weeks. Fractional exhaled nitric oxide (FeNO) and pulmonary function were measured, and quantitative computed tomography was performed. Results : Compared to the maintenance therapy, add-on montelukast significantly decreased FeNO ( p  < 0.05) and improved airflow obstruction ( p  < 0.05), whereas airway dimensions remained unchanged. Changes in FeNO were significantly correlated with changes in FEV 1 ( r  = -0.71, p  < 0.001). In contrast, the addition of tiotropium significantly decreased airway wall area corrected for body surface area (WA/BSA) ( p  < 0.05), decreased wall thickness (T/√BSA) ( p  < 0.05) and improved airflow obstruction ( p  < 0.05) with no change in FeNO. Changes in WA/BSA and T/√BSA were significantly correlated with the change in percentage predicted FEV 1 ( r  = -0.84, p  < 0.001 and r  = -0.59, p  < 0.01, respectively). Conclusions :Adding either montelukast or tiotropium to ICS/LABA may provide additive benefits with respect to the pulmonary function and airway inflammation or remodeling in patients with asthma.

Background: Tiotropium, a once-daily, long-acting anticholinergic bronchodilator, has shown efficacy and safety as an add-on to maintenance therapy in patients with symptomatic asthma., Objective: The aim of the present study was to assess the effect of tiotropium on airway geometry and airway inflammation in patients with asthma who were symptomatic despite treatment with inhaled corticosteroid (ICS) plus a long-acting beta 2agonist (LABA)., Methods: In total, 53 patients with symptomatic asthma who received ICS plus LABA and who had a prebronchodilator forced expiratory volume in 1 second of 6090% of the predicted value were randomized to the addition of tiotropium 5 g once daily (n = 25) or no add-on (n = 28) to maintenance therapy for 48 weeks. Quantitative computed tomography, fractional exhaled nitric oxide, and pulmonary function were measured., Results: Compared with maintenance therapy, the addition of tiotropium significantly decreased airway wall area (WA) corrected for body surface area (BSA) (WA/BSA) (p 0.05) and wall thickness (T) (T/BSA, p 0.05), and improved airflow obstruction. No significant difference in the change of fractional exhaled nitric oxide was observed between the two treatment groups. Changes in WA/BSA and T/BSA were significantly correlated with the change in predicted forced expiratory volume in 1 second (r = 0.87, p 0.001, and r = 0.82, p 0.001, respectively)., Conclusion: The addition of once-daily tiotropium to maintenance therapy improved airflow limitation and reduced airway T. A triple combination of tiotropium and ICS plus LABA may have additive protective effects of bronchodilation and remodeling.

Background: Periostin may be a useful biomarker of T-helper type 2 eosinophilic airway inflammation and has been linked to remodeling in asthma. However, the association between serum periostin and the magnitude of airway wall thickness remains unclear., Objective: We examined the relationship between serum periostin and airway geometry in asthma., Methods: Twenty-six patients with steroid-naive asthma, 30 patients with asthma treated with inhaled corticosteroids, and 46 aged-matched healthy controls were studied. Serum periostin levels, lung function, and inflammatory cell counts in sputum were measured. The following parameters of airway dimension were assessed by computed tomography: lumen area, wall area (WA), WA to total area ratio, and wall thickness., Results: Serum periostin levels were significantly elevated in patients with steroid-naive asthma compared with the controls (p < 0.01) and patients with asthma who were treated with steroids (p < 0.01). In patients who were steroid naive, serum periostin was correlated with air flow limitation (r = -0.62, p < 0.01) and the WA to body surface area (r = 0.71, p < 0.01), and sputum eosinophil percentage (r = 0.60, p < 0.01). Multivariate analysis showed that the percentage of predicted forced expiratory volume in 1 second, WA to body surface area, and sputum eosinophils were independent factors for high serum periostin., Conclusion: Serum periostin may be a candidate for a novel biomarker for not only eosinophilic inflammation but as a marker for airway remodeling in asthma.

Background and Objective: Periostin is a biomarker of eosinophilic airway inflammation and may contribute to airway remodeling in asthma. The anti-inflammatory activity of inhaled corticosteroids (ICS) for asthma control is widely recognized. The aim of this study was to assess the effects of ICS on serum periostin levels and its relationships to inflammation and airway geometry., Methods: Forty-two healthy controls and 20 patients with steroid-naïve asthma before and after treatment with fluticasone propionate (800 μg/day for 16 weeks) were examined. Serum periostin, lung function and inflammatory cell counts in sputum were measured. Airway dimensions were determined by quantitative computed tomography (total area of the airway (Ao), wall area (WA), wall thickness (T) and percentage wall area (WA%) )., Results: Serum periostin concentrations were significantly higher in patients with asthma than in controls. Periostin levels were correlated with airway wall thickness and sputum eosinophilia and inversely correlated with airflow limitation in asthma. ICS significantly decreased serum periostin (P < 0.01), decreased WA corrected for body surface area (WA/BSA, P < 0.05), T/√BSA (P < 0.01) and WA% (P < 0.01), reduced the percentage of sputum eosinophils (P < 0.01) and improved airflow limitation. The decrease in serum periostin levels was associated with an increased per cent predicted forced expiratory volume in 1 s (r = -0.64, P < 0.01), decreased WA/BSA (r = 0.46, P < 0.05) and decreased sputum eosinophils (r = 0.71, P < 0.01)., Conclusion: Serum periostin levels respond partially to ICS and may reflect a reduction in airway inflammation and wall thickening in asthma., (© 2015 Asian Pacific Society of Respirology.)

Background: Asthma is characterized by chronic airway inflammation and remodeling. Levels of serum high-sensitivity C-reactive protein (hs-CRP) reflect airway eosinophilic inflammation. However, the relation between hs-CRP and the development of airway wall thickening remains unknown., Objective: To evaluate whether serum hs-CRP is associated with airway geometry in asthma., Methods: Forty-eight steroid-naive patients with asthma, 51 patients with asthma treated with inhaled corticosteroids, and 38 aged-matched healthy controls were studied cross-sectionally. Serum hs-CRP levels, lung function, and inflammatory cell counts in sputum were measured. Quantitative computed tomographic analysis of the apical segment of the right upper lobe was performed., Results: Serum hs-CRP levels were significantly elevated in steroid-naive patients with asthma compared with controls and steroid-treated patients with asthma and were associated with airflow limitation. In steroid-naive patients, serum hs-CRP levels were correlated with airway wall thickness (r = 0.88, P < .001) and sputum eosinophil percentage (r = 0.75, P < .001). Multivariate analysis showed a significant association between hs-cRP levels and forced expiratory volume in 1 second (percentage predicted; R(2) = 0.65, P = .001)., Conclusion: Serum hs-CRP may be a useful systemic biomarker of airway eosinophilia in steroid-naive asthma and has potential utility as a marker for the development of airway wall thickening., Trial Registration: University Hospital Medical Information Network (www.umin.ac.jp/ctr/index/htm); identifier, UMIN000006724., (Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Combination therapy with inhaled corticosteroids and long-acting β(2)-agonists results in improved asthma symptom control compared with the use of inhaled corticosteroids alone. However, the effects of combination therapy on structural changes and inflammation of the airways are still unknown. The aim of this study was to compare the effects of budesonide/formoterol with those of budesonide alone on airway dimensions and inflammation in individuals with asthma., Methods: Fifty asthmatic patients were randomized to treatment with budesonide/formoterol (200/6 µg, two inhalations bd) or budesonide (200 µg, two inhalations bd) for 24 weeks. Airway dimensions were assessed using a validated computed tomography technique, and airway wall area (WA) corrected for body surface area (BSA), percentage WA (WA%), wall thickness/Ösquare root BSA, and luminal area (Ai)/BSA at the right apical segmental bronchus, were measured. The percentage of eosinophils in induced sputum, pulmonary function, and Asthma Quality of Life Questionnaires (AQLQ) were also evaluated., Results: There were significantly greater decreases in WA/BSA (P < 0.05), WA% (P < 0.001) and wall thickness/square root BSA (P < 0.05), and increases in Ai/BSA (P < 0.05), in subjects treated with budesonide/formoterol compared with those treated with budesonide. The reduction in sputum eosinophils and increase in per cent of predicted forced expiratory volume in 1 s (FEV(1) %) were greater for subjects treated with budesonide/formoterol compared with those treated with budesonide alone. In the budesonide/formoterol group, the changes in WA% were significantly correlated with changes in sputum eosinophils and FEV(1%) (r = 0.84 and r = 0.64, respectively). There were improvements in the AQLQ scores after treatment with budesonide/formoterol., Conclusions: Budesonide/formoterol combination therapy is more effective than budesonide alone for reducing airway wall thickness and inflammation in individuals with asthma., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

Background: Omalizumab may inhibit allergic inflammation and could contribute to decreasing airway remodeling in patients with asthma., Objective: The aim of this study was to assess the effects of omalizumab on airway wall thickness using computed tomography (CT)., Methods: Thirty patients with severe persistent asthma were randomized to conventional therapy with (n = 14) or without omalizumab (n = 16) for 16 weeks. The following airway dimensions were assessed by a validated CT technique: airway wall area corrected for body surface area (WA/BSA), percentage wall area (WA%), wall thickness (T)/√BSA, and luminal area (Ai)/BSA at the right apical segmental bronchus. The percentage of eosinophils in induced sputum, pulmonary function and the Asthma Quality of Life Questionnaire (AQLQ) were assessed as well., Results: Treatment with omalizumab significantly decreased WA/BSA (p < 0.01), WA% (p < 0.01), and T/√BSA (p < 0.01), and increased Ai/BSA (p < 0.05), whereas conventional therapy resulted in no change. In the omalizumab group (n = 14), a significant decrease in the percentage of sputum eosinophils (p < 0.01), improved forced expiratory volume in 1 s (FEV(1)), and an improved AQLQ score were recorded. The changes in FEV(1)% predicted and sputum eosinophils were significantly correlated with changes in WA% (r = 0.88, p < 0.001, and r = 072, p < 0.01, respectively)., Conclusions: These findings suggest that omalizumab reduced airway wall thickness and airway inflammation. Larger patient studies with longer-term follow-up are needed to show whether omalizumab can truly maintain improved airway wall dimensions., (Copyright © 2012 S. Karger AG, Basel.)

Background: Asthma is characterized by variable airflow obstruction and airway wall thickening. Multidetector-row computed tomography (MDCT) is useful for the evaluation of airway wall structural changes in asthma. The objective of the study is to assess the relationship between airflow limitation and airway dimensions from the third to fifth generation bronchi in asthma using MDCT., Methods: Thirty-eight subjects with asthma underwent MDCT to measure the airway wall area (WA) and luminal area (Ai), WA and Ai corrected by body surface area (BSA), up to the fifth generation of the apical bronchus (B1) and the posterior basal bronchus (B10) of the right lung., Results: WA/BSA, WA percentage (WA%) and Ai/BSA in the fifth generation were significantly correlated with forced expiratory volume in 1 s (FEV(1))% predicted. The correlation coefficients between WA% and FEV(1)% predicted increased when tracking the airways from the third to the fifth generation (r=-0.25, p>0.05; r=-0.40, p<0.01; r=-0.63, p<0.001 for B1; r=-0.23, p>0.05; r=-0.47, p<0.01; r=-0.69, p<0.001 for B10). At the generation 5, WA% was greater and Ai/BSA was smaller in severe asthma than mild-to-moderate asthma., Conclusion: These results suggest that airway flow limitation in asthma is closely related to the more distal airways (third to fifth generation)., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: Salmeterol and fluticasone propionate combination (SFC) provides better asthma control than fluticasone propionate (FP) alone, however, little is known on the effects of differential treatments on airway function and inflammation in patients with mild asthma., Methods: We randomized 27 mild persistent asthma patients treated with the equivalent of 400 microg beclomethasone dipropionate to receive SFC (50/100 microg , 13 patients) or FP (100 microg , 14 patients) twice daily for 8 weeks. We compared the effects of SFC and FP on pulmonary function assessed by spirometry and impulse oscillometry (IOS), eosinophil percentage of induced sputum and serum, and with asthma symptoms and control after each treatment., Results: We observed that SFC significantly improved forced expiratory volume in one second (p < 0.05), IOS measurements of total resistance R5 (p < 0.01), central resistance R20 (p < 0.05), and distal reactance X5 (p < 0.01) compared with FP. The percentage of eosinophils in sputum, but not in serum, decreased significantly more in the SFC group than in the FP group (p < 0.05). There was also a significant improvement in symptom control in the SFC group (p < 0.05)., Conclusions: These findings suggest that SFC is more useful than FP in mild asthma cases. The clinical benefit of SFC provides evidence that IOS and induced sputum allows for the detection of changes in airway function and inflammation.

Background: Goblet cell metaplasia is a pathologic characteristic of asthma, associated with excess mucus secretion. Interleukin (IL)-4 and IL-13 plays an important role in mucus hypersecretion. Suplatast tosilate (suplatast), an antiallergic agent, is a Th2 cytokine inhibitor that suppresses the synthesis of IL-4, IL-5, IL-13, and eosinophilic airway inflammation., Objective: We examined the effects of suplatast on mucus production in bronchial biopsy specimens taken from asthmatic subjects., Methods: Oral suplatast 300 mg daily, or placebo was administered for 3 months in a double-blind, parallel-group study in 25 patients with asthma. Biopsy specimens were evaluated at before and after treatment for alcian blue/period acid-Schiff (AB/PAS), MUC5AC staining in bronchial epithelium and IL-4+, IL-13+ cells as well as inflammatory cells in lamina propria., Results: There were significant decreases in the percentage of AB/PAS (P < 0.01) and MUC5AC (P < 0.01) stained area in the suplatast group. These changes were accompanied by significant decreases in IL-4+ and IL-13+ cells in suplatast-treated subjects. Additionally, we have observed that the number of infiltrating eosinophils and CD4+ T cells significantly decreased., Conclusions: These findings suggest that suplatast prevents goblet cell metaplasia through modulation of Th2 cytokine production and the recruitment of eosinophils and CD4+ T cells in the asthmatic airways.

The increasing levels of morbidity and mortality due to the rising prevalence of asthma and other allergic diseases have inspired investigations of several new molecular techniques to improve treatment. Recently, several preclinical studies have been published which utilize attributes or facets of DNA to address asthma therapy. These novel therapeutics include antisense oligonucleotides against TH2 cytokines and associated transcription factors. While no clinical experience has yet been reported for any of these areas of research in asthma, specific small molecule inhibitors of TH2 cell responses would be desirable for treatment of this chronic disease. Six transcription factors (c-Maf, NF-AT, NF-IL-6, AP-1, STAT-6 and GATA-3) have been implicated in the differentiation of TH2-type lymphocytes and therefore, in addition to TH2-type cytokines, represent therapeutic targets for asthma. This review will focus on new research involving suppression of Th2-type cytokines and associated transcription factors using antisense and decoy oligonucleotides. Recently, novel oligonucleotides have been devised to improve stability in vitro and in vivo stability against nucleases, and the efficacy of these approaches will also be presented.

Background: Bronchial asthma is characterized by airway inflammation, notably because of eosinophils and T cells. Thymus and activation-regulated chemokine (TARC) is known to selectively attract Th2 cells, and is increased in response to interleukin (IL)-4 and IL-13, which share a common receptor, IL-4 receptor alpha (IL-4Ralpha). While corticosteroids have proven, very effective in modifying airway inflammation, the effect of corticosteroids on TARC in asthmatics has been little studied., Objective: We examined the effects of inhaled budesonide (BUD) on the expression of TARC and the number of inflammatory cells in bronchial biopsy specimens taken from asthma patients., Methods: Inhaled BUD 800 mug daily, or placebo was administered for 3 months in a double-blind, parallel-group study, and bronchial biopsies were performed before and after treatment. Biopsy specimens were examined by immunocytochemistry., Results: We observed a significant decrease in the epithelial expression of TARC (P < 0.01) in the BUD group compared with the placebo group. This was accompanied by decreases in the number of eosinophils (P < 0.01), CD3(+) T cells (P < 0.05), and CD4(+) T cells (P < 0.01). A significant correlation was found between changes in epithelial TARC and in IL-4Ralpha immunoreactivity (r(s) = 0.66, P < 0.01)., Conclusions: These findings suggest that corticosteroid asthma treatment can reduce infiltration of the airway by inflammatory cells, an effect modulated by down-regulation of bronchial epithelial TARC expression.

Asthma is a chronic inflammatory disease of the airways that is characterized by the presence of inflammatory cells and remodeling, a term used to define complex morphological changes involving all the structures of the bronchial wall (e.g., goblet cell hyperplasia of the epithelium, thickening of reticular basement membrane, increases of airway smooth muscle[ASM], and blood vessels). An important factor in the pathophysiology of asthma is the recognition that airway inflammation and airway remodeling are linked, as they are in other chronic inflammatory diseases. First-line therapy of persistent asthma involves the use of inhaled corticosteroids to control the underlying inflammation of the airways. Because remodeling of the airway wall is thought to be a result of chronic inflammation within the bronchial wall, it follows that because steroids reduce or reverse inflammation, they may also prevent or modulate remodeling. It has been revealed that steroids improve the subepithelial fibrosis and also significantly reduce airway vascularity. The cysteinyl leukotrienes receptor antagonists may also be helpful regarding the targeting of the inflammation and remodeling in asthma. However,long-term studies were needed to appreciate the prevention and treatment of remodeling by drug therapies.

Stromal cell-derived factor-1 (SDF-1) acts as a chemoattractant for leukocytes and can induce neovascularisation. To examine the role of SDF-1 in the development of angiogenesis, immunohistochemical studies were performed on bronchial biopsy specimens from asthmatic and control subjects. Bronchial biopsy specimens were obtained from 13 asthmatic and eight control subjects. The number of vessels and the percentage area they occupied were estimated after staining for type-IV collagen. In addition the number of SDF-1-positive cells was determined. There was a significant increase in the number of vessels and the percentage vascularity in the submucosa of asthmatic subjects compared with control subjects. Asthmatic subjects exhibited a greater number of SDF-1-positive cells in the airway mucosa than control subjects. The degree of vascularity was associated with the number of SDF-1-positive cells. Furthermore, the number of SDF-1-positive cells was inversely correlated with airway calibre and airway hyperresponsiveness. Colocalisation studies revealed that endothelial cells, macrophages and T-lymphocytes were the major sources of SDF-1. These findings suggest that increased vascularity of bronchial mucosa in asthmatic subjects is closely related to the expression of stromal cell-derived factor-1 positive cells, which may play a role in remodelling of airways via angiogenesis.

Mucus overproduction is a clinical feature of asthma. Ca2+-activated Cl- channel 1 (CaCC1) has been identified as a protein that is expressed in intestinal epithelia and that plays an important role in fluid and electrolyte transport. Recently, its mouse counterpart, gob-5, was identified as a key molecule in the induction of murine asthma through mucus overproduction. To elucidate the relationship of CaCC1 to human asthma, we examined CaCC1 expression using real-time quantitative polymerase chain reaction analysis in bronchial tissues from patients with asthma and normal control subjects. The expression of CaCC1 was significantly upregulated in patients with bronchial asthma compared with control subjects. In situ hybridization and immunohistochemical analysis demonstrated that CaCC1 is located in the bronchial epithelium, especially in mucus-producing goblet cells. In vitro transfection of a CaCC1 expression vector into the human mucoepidermoid cell line, NCI-H292, increased mucus production and induced the MUC5AC gene. These results suggest that CaCC1 plays a direct role in mucus production and differentiation in goblet cells and may contribute to the pathogenesis of asthma through its mucus-inducing activity.

Background: Angiogenesis is a feature of airway remodeling in bronchial asthma. The mechanism responsible for this angiogenesis is unknown. Vascular endothelial growth factor (VEGF) is a potent inducer of endothelial cells, which may contribute to chronic inflammation and angiogenesis., Objective: We sought to investigate the molecular mechanisms underlying increased vascularity, and we examined the mRNA expression of VEGF and its receptors (flt-1 and flk-1) within bronchial biopsy specimens from asthmatic patients and normal control subjects., Methods: Endobronchial biopsy specimens were examined immunocytochemically by staining with anti-type IV collagen mAb to evaluate vessel density by using computer-assisted image analysis. Specimens were also analyzed for the presence of the mRNAs of VEGF and its receptors with in situ hybridization., Results: The extent of airway vascularity was increased in asthmatic subjects compared with that in control subjects (P <.01). Asthmatic subjects exhibited a greater expression of VEGF, flt-1, and flk-1 mRNA(+) cells in the airway mucosa compared with that in control subjects (P <.001 for each comparison). The degree of vascularity was associated with the number of VEGF, flt-1, and flk-1 mRNA(+) cells. Numbers of cells expressing VEGF mRNA inversely correlated with airway caliber (r = -0.83, P <.01) and airway hyperresponsiveness (r = -0.97, P <.001). Colocalization studies showed that macrophages, eosinophils, and CD34(+) cells were the major sources of VEGF; CD34(+) cells, macrophages, and T cells expressed both flt-1 and flk-1., Conclusion: These findings provide evidence that VEGF may play an important role in angiogenesis and subsequent airway remodeling in bronchial asthma.

Background: Increased vascularity in airway mucosa is a distinctive feature of airway remodelling in asthma. While corticosteroids have proved most effective in modifying airway inflammation, the effect of inhaled corticosteroids on increased airway mucosal vascularity in asthmatics has been little studied., Objective: We examined the effect of inhaled corticosteroid on airway vascularity in bronchial biopsy specimens taken from asthmatic patients., Subjects and Methods: We studied bronchial biopsies from 28 asthmatic patients before and after treatment with inhaled beclomethasone dipropionate (BDP) 800 microg/daily, or placebo, for 6 months in a double-blind manner. Biopsy specimens were evaluated for number of vessels and percentage of area occupied by vessels, using computerized image analysis after staining for type IV collagen in vessel walls. Specimens were also examined for extent of collagen III in the subepithelial basement membrane. In addition, we compared asthmatic specimens with biopsy specimens taken from non-asthmatic control subjects., Results: There was a significant increase in number of vessels (P < 0.01) and percent vascularity (P < 0.001) in the submucosa of asthmatic patients compared with control subjects. After 6 months of treatment, we observed significant improvements in forced expiratory volume in 1 s (FEV1), FEV1% and airway responsiveness (P < 0.05, each) in the BDP treatment group compared with the placebo group. This was accompanied by significant decreases in both vessel number and percent vascularity in the airways of BDP-treated patients (P < 0.05, each). We also observed a significant correlation between change in percent vascularity and change in collagen III thickness in the BDP-treated patients (rs = 0.90, P < 0.001). Furthermore, the change in percent vascularity was inversely correlated with both FEV1 (rs = -0.49, P < 0.05) and airway responsiveness (rs = -0.36, P < 0.05)., Conclusion: These findings suggest that inhaled corticosteroid treatment of asthma reduced airway wall vascularity during airway remodelling.

Background: Angiogenesis is a prerequisite for airway remodeling in bronchial asthma. Several growth factors may play important roles in inflammation and angiogenesis through effects on inflammatory cell infiltration or neovascularization., Objective: We sought to compare bronchial vascularity and expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin in bronchial biopsy specimens from asthmatic and healthy control subjects., Methods: Bronchial biopsy specimens were obtained from 16 asthmatic subjects and 9 normal control subjects. The number of vessel profiles and the vascular area per unit area on a histologic section were estimated by using computerized image analysis after staining for type IV collagen in vessel walls. Numbers of VEGF+, bFGF+, and angiogenin+ cells were determined by means of immunoreactivity., Results: The airways of asthmatic subjects had significantly more vessels (P < .05) and greater vascular area (P < .001) than that observed in control subjects. Asthmatic subjects exhibited higher VEGF and bFGF and angiogenin immunoreactivity in the submucosa than did control subjects (P < .001, respectively). Significant correlations were detected between the vascular area and the numbers of angiogenic factor-positive cells (VEGF: rs = 0.93, P < .001; bFGF: rs = 0.83, P < .001; angiogenin: rs = 0.88, P < .001) within the asthmatic airways. Furthermore, the degree of vascularity was inversely correlated with airway caliber and airway responsiveness. Colocalization analysis revealed that the angiogenic factor-positive cells were CD34+ cells, eosinophils, and macrophages., Conclusion: Our results suggest that increased vascularity of the bronchial mucosa in asthmatic subjects is closely related to the expression of angiogenic factors, which may then contribute to the pathogenesis of asthma.

Background: Bronchial asthma is characterized by airway wall remodeling. Matrix metalloproteinases (MMPs) are members of a family of proteolytic enzymes that degrade the extracellular matrix and that restrain the effects of their tissue inhibitors (TIMPs). Treatment with inhaled corticosteroids may prevent airway remodeling in asthma. However, the effects of corticosteroid treatment on MMPs and TIMPs in asthma are unknown., Objective: We examined the effects of inhaled beclomethasone dipropionate (BDP) on the expression of MMP-9 and TIMP-1 and subepithelial collagen deposition in bronchial biopsy specimens from 30 subjects with asthma., Methods: Inhaled BDP, 800 microg daily, or placebo was administered for 6 months in a double-blind, parallel-group study, and bronchial biopsies were performed before and after treatment. Biopsy specimens were examined for extent of collagen type III in the subepithelial basement membrane by means of immunohistochemistry, and expression of both epithelial and submucosal MMP-9 and TIMP-1 was quantitated. Numbers of inflammatory cells were also determined., Results: We observed significant decreases in collagen type III deposition (P <.01) and the expression of submucosal MMP-9 (P <.01) and a significant increase in the expression of submucosal TIMP-1 (P <.05) in the BDP group. Significant correlations were found between the subepithelial collagen type III deposition and epithelial (r (s ) = 0.37, P <.05) and submucosal expression of MMP-9 (r (s ) = 0.47, P <.01). Additionally, the number of many inflammatory cells and myofibroblasts in airway mucosa were significantly decreased in the BDP group., Conclusion: Our findings suggest that corticosteroid treatment of asthma can reduce subepithelial collagen deposition by downregulation of MMP-9 expression and upregulation of TIMP-1 expression.

Background: Asthma is a chronic inflammatory disease of the airways. The chemokines are potent chemoattractants for eosinophils and other types of cells associated with allergic inflammation. AA-2414, a new thromboxane A2 receptor antagonist, reduces bronchial hyperresponsiveness in asthmatic subjects, but its mechanism of action is unclear., Objective: We tested the hypothesis that the beneficial effects of AA-2414 in asthma result from reduction in the number of inflammatory cells infiltrating the airway associated with inhibition of chemokine release., Methods: We studied bronchial biopsy specimens from 31 asthmatic subjects before and after oral treatment with AA-2414 (80 mg/day) or matched placebo for 4 months in a double-blind manner. Biopsy specimens were examined by immunohistochemistry. Each subject recorded symptom score and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment., Results: After treatment, significant improvements in symptom score (P <.05), PEF (P <.01), diurnal variation of PEF (P <.01), and bronchial responsiveness (P <.01) were observed in the AA-2414 group compared with the placebo group. These improvements were accompanied by a significant decrease in the number of submucosal EG2(+) eosinophils (P <.05). There was also a reduction in the number of cells expressing RANTES (P <.05) and macrophage inflammatory protein (MIP)-1alpha (P <.05) in the epithelium and of cells expressing monocyte chemotactic protein-3 (P <.01), RANTES (P <.05), MIP-1alpha (P <.01), and eotaxin (P <.01) in the submucosa in the AA-2414 treatment group. A significant correlation was found between the number of EG2(+) eosinophils and numbers of monocyte chemotactic protein-3(+) (rs = 0.52, P <.005), MIP-1alpha+ (rs = 0.34, P <.05), and eotaxin+ cells (r s = 0.47, P <.01) in the submucosa. There was a significant negative correlation between the increase in bronchial responsiveness and the change in number of submucosal EG2(+) cells (rs = -0.65, P <.001)., Conclusions: These findings suggest that AA-2414 treatment of patients with asthma may inhibit activated eosinophil infiltration in part by modulating the expression of chemokines in bronchial tissues.

Background: Bronchial asthma is characterized by airway structural changes, including mucosal inflammation and subepithelial collagen deposition. An imbalance between the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is thought to play a critical role in the synthesis or degradation of the extracellular matrix of the airway architecture. However, the relationship between subepithelial basement membrane thickness and these enzymes in asthma has not been determined., Objective: We compared the thickness of collagen and tenascin deposition and the expression of MMP-9 and TIMP-1 in bronchial biopsy specimens from subjects with asthma and control subjects., Methods: Bronchial biopsy specimens were obtained from 25 subjects with asthma and 10 healthy control subjects to estimate the extent of collagen and tenascin deposition in subepithelial reticular basement membrane by immunohistochemical staining. Using a computer-assisted image analysis system, we quantitated expression of both epithelial and submucosal MMP-9 and TIMP-1. The numbers of inflammatory cells were also determined., Results: Subjects with asthma exhibited greater thickness of collagen III (P <.01), collagen V (P <.01), and tenascin (P <.01) deposition in reticular basement membrane than did control subjects. The proportions of epithelium and submucosa immunoreactive to MMP-9 and TIMP-1 were significantly higher in the subjects with asthma than in the control subjects (each P <.001). Submucosal expression of MMP-9 was significantly higher than that of TIMP-1 in subjects with asthma (P <.01). Significant correlations were found between the number of myofibroblasts and thicknesses of collagen III (rs = 0. 70, P <.001), collagen V (rs = 0.67, P <.001), and tenascin (rs = 0. 58, P <.01) in subjects with asthma. On the other hand, the number of eosinophils was correlated with degree of mucosal expression of MMP-9 (rs = 0.43, P <.05) and TIMP-1 (rs = 0.69, P <.001). In subjects with asthma, a significant inverse correlation was found between subepithelial fibrosis and FEV1 (type III collagen, rs = -0. 89, P <.001; type V collagen, rs = -0.90, P <.001; tenascin, rs = -0. 88, P <.001), and airway responsiveness (type III collagen, rs = -0. 59, P <.01; type V collagen, rs = -0.47, P <.05; tenascin, rs = -0. 48, P <.05)., Conclusion: These findings suggest that collagen III, collagen V, and tenascin deposition in basement membrane in subjects with bronchial asthma are associated with increased expression of MMP-9, which may be produced by eosinophils, and that airway remodeling in subjects with asthma may be related to air-flow obstruction and airway hyperresponsiveness.

Background: It has been reported that pranlukast reduces the antigen induced immediate and late phase asthmatic responses, airway hyperreactivity to acetylcholine, and pulmonary eosinophil accumulation in guinea pigs. A study was undertaken to test the hypothesis that pranlukast may reduce the number of inflammatory cells in the bronchial mucosa of patients with asthma., Methods: A double blind, placebo controlled study was performed in 17 mild to moderate asthmatic subjects to examine changes in inflammatory cell infiltration in response to pranlukast (225 mg orally twice per day for four weeks). Comparisons of the mean daily beta 2 agonist use, symptom score, FEV1 percentage predicted, and airway methacholine responsiveness were made before and after treatment. Using fibreoptic bronchoscopy, bronchial biopsy specimens were obtained before and after treatment with either pranlukast (n = 10) or placebo (n = 7). Immunohistology was performed using monoclonal antibodies for CD3, CD4, CD8, CD68, NP57, AA1, EG1, EG2, gamma GTP and CD19., Results: When the pranlukast and placebo treated groups were compared there were decreases in beta 2 agonist use, symptom score, and airway methacholine responsiveness after pranlukast but no increase in FEV1 was seen. The clinical response in patients treated with pranlukast was accompanied by a reduction in CD3 (median difference -37, 95% confidence interval (CI) -69 to -1; p < 0.05), CD4 (median difference -28, 95% CI -49 to -8; p < 0.01), AA1 (median difference -15, 95% CI -26 to 0; p < 0.05) and EG2 positive cells (95% CI -35 to 0; p < 0.05), but not in EG1 positive eosinophils, gamma GTP positive cells, and CD19 positive plasma cells., Conclusions: These results support the view that pranlukast may act by inhibition of bronchial inflammation in patients with asthma.

Asthma is a chronic inflammatory disorder of the airways that is characterized by infiltration of many inflammatory cells into the bronchial mucosa. We compared the effects of ketotifen, disodium cromoglycate (DSCG), and beclomethasone dipropionate (BDP) on inflammatory cells in the bronchial mucosa and on the asthma symptoms of patients with atopic asthma. In this 12-week parallel study, 32 patients were randomly allocated to either the ketotifen group (2 mg day-1, n = 13), DSCG group (8 mg day-1, n = 9) or BDP (400 micrograms day-1, n = 10). Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Before and after treatment, pulmonary function and bronchial responsiveness to methacholine were evaluated, and fibreoptic bronchoscopy and biopsy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. We performed immunohistochemistry using specific monoclonal antibodies for activated eosinophils (EG2), mast cells (AA1), and T cells (CD3, CD4, and CD8). Our clinical findings showed significant improvement in symptom score and bronchial responsiveness (P < 0.01) each) in all groups. Both the DSCG and the BDP groups had significantly better symptom scores than the ketotifen group (P < 0.05, both groups). PEF significantly increased in the DSCG group in comparison to the ketotifen (P < 0.01) and BDP (P < 0.05) groups, FEV1% increased significantly in the DSCG (P < 0.01) and BDP (P < 0.05) groups in comparison to the ketotifen group. Compared with their baseline values, treatment significantly decreased EG2+ activated eosinophils, and CD3+ and CD4+ T cells, in each group (P < 0.01). Both the DSCG (P < 0.05) and the BDP groups (P < 0.01) exhibited significant decreases in AA1+ mast cell count, but this was not observed in the ketotifen group. Comparing before- and after-treatment values, only the DSCG group exhibited a significant decrease in the number of CD8+ T cells (P < 0.01). Ketotifen, DSCG, and BDP all showed anti-inflammatory activity as determined by examination of the bronchial mucosa of asthmatic patients; and both the DSCG and BDP groups had better clinical responses than the ketotifen group.

Background: Pathological studies of bronchial biopsy specimens have confirmed the apparent thickening of lamina reticularis of the epithelial basement membrane. Corticosteroids have proven to be most effective in modifying airway inflammation. However, there is not much data on the effects of corticosteroid-treatment on the basement membrane., Objective: To investigate the effects of inhaled beclomethasone dipropionate (BDP) on the thickness of basement membrane and cellular infiltration into the bronchial mucosa, and the expression of growth factors in patients with asthma., Methods: We studied bronchial biopsies from 24 asthmatic patients before and after treatment with inhaled BDP, 400 microg twice a day or placebo, for 6 months in a double-blind manner. Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. The thickness of the basement membrane was determined by electron microscopy. Inflammatory cells and the expression of growth factors were examined by immunohistochemistry in endobronchial biopsy specimens., Results: After 6 months of treatment, we observed a significant improvement of asthma symptoms (P<0.01), PEF (P<0.01), diurnal variation of PEF (P<0.05), and airway responsiveness (P< 0.05) in the BDP group compared with the placebo group. This was accompanied by a significant decrease in the thickness of the lamina reticularis (P < 0.001), and in the number of activated eosinophils (P<0.01), T-lymphocytes (P<0.01), and fibroblasts (P < 0.05) in BDP-treated patients. There was also a reduction in the expression of insulin-like growth factor (IGF)-I (P < 0.01). Significant correlation was found between the IGF-I expression and collagen thickening (rs = 0.34, P<0.01), and the number of fibroblasts (rs = 0.45, P < 0.01)., Conclusion: These results suggest that corticosteroid treatment in asthma can reduce the lamina reticular thickness by modulation of IGF-I expression with consequent inhibition of the airway infiltration by inflammatory cells, and therefore may help to prevent remodelling of the airways.

Cough variant asthma (CVA) is thought to be a variant form of asthma in which cough is the sole clinical manifestation of airways hyperresponsiveness, a characteristic feature of asthma. Another characteristic feature of asthma includes an increased diurnal variation of peak expiratory flow (PEF) compared to normal subjects. To examine whether diurnal variation of PEF might also increase in children with CVA, we have examined the degree of diurnal variation of PEF in these children (n = 7) by measuring peak flow serially for a week, and compared it with those in mild to moderate asthma (n = 17) and in control children without cough (n = 8). In control children without cough, the average value of the mean diurnal variation of PEF was 10.4 +/- 0.8%. In both groups of children with asthma and with CVA, there was a significant increase in the value (20.5 +/- 1.3% and 23.6 +/- 3.6%, respectively) compared to that in control children (p < 0.01 in both groups), although there was no significant difference between these 2 groups. These results show that mild, but significant airway obstruction is occurring in children with CVA, although clinical wheezing is not recognized. Serial measurements of diurnal variation of PEF may be helpful for the diagnosis of CVA in children.

Background: Bronchial asthma is characterised by airway structural changes, including mucosal inflammatory infiltration and subepithelial collagen deposition, that may represent the morphological basis for the chronicity of the disease. The relationship between airway wall thickness and growth factors in asthma has not been elucidated., Methods: Bronchial biopsy specimens were obtained from 21 asthmatic patients and eight healthy subjects and the basement membrane thickness was measured by light microscopy and electron microscopy. At the same time the numbers of eosinophils and fibroblasts were assessed and the expression of transforming growth factor beta 1 (TGF-beta 1), platelet derived growth factor (PDGF), and insulin like growth factor (IGF) I in the bronchial mucosa was examined by immunostaining. The relationship between the degree of thickening of the subepithelial layer and both the clinical data and pulmonary function were also investigated., Results: The basement membrane of the asthmatic patients was thicker than that of the healthy controls (median 8.09 versus 4.02 microns). Electron microscopic examination of the basement membrane revealed thickening of the subepithelial lamina reticularis; this thickening significantly correlated with the number of fibroblasts in the submucosa in the asthmatic subjects (rs = 0.88) but not in the controls (rs = 0.70). There was a significantly higher number of eosinophils in the airways of the asthmatic subjects than in the healthy subjects (EG1 + cells: 52.0 versus 2.0/mm2, EG2 + cells: 56.0 versus 1.5/mm2). The expression of each growth factor in the bronchial mucosa was similar in asthmatic and healthy subjects (TGF-beta 1: 18.0% versus 16.0%, PDGF: 37.0% versus 32.5%, IGF-I: 15.0% versus 8.0%). A weak but statistically significant correlation was found between the number of fibroblasts and the expression of TGF-beta 1 in asthmatic subjects (rs = 0.50). There was a significant correlation between the thickness of the subepithelial layer in asthmatic subjects and the attack score (rs = 0.58) and a significant inverse correlation between the subepithelial collagen thickness in asthmatic subjects and airway hypersensitivity (rs = -0.65)., Conclusions: These findings indicate that the thickening of the subepithelial layer in bronchial asthma is due to an increase in fibroblasts, and that the thickness of the subepithelial collagen appears to be linked to an increase in bronchial responsiveness and exacerbation of clinical manifestations.

Background: Azelastine is an oral antiallergic compound but there is no direct evidence of its anti-inflammatory actions in bronchial asthma. We examined the effect of azelastine on inflammatory cells infiltrating the bronchial mucosa and clinical symptoms in atopic asthma in a double-blind, parallel, randomized study., Methods: The study was completed by 13 subjects in the azelastine (4 mg/day) group and 11 subjects in the placebo group. Treatments were randomly administered for 3 months. Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. Fiberoptic bronchoscopy was performed and bronchial biopsies taken from segmental carinae before and after treatment with azelastine or placebo. Using each monoclonal antibody for eosinophils, mast cells, macrophages, and T lymphocytes we performed immunohistological staining on biopsy specimens., Results: Compared with the placebo-treated group, the azelastine-treated group exhibited significant improvement of asthma symptoms (p<0.01), PEF (p<0.01), PEF diurnal variation (p<0.001), excluding forced expiratory volume in 1 s or airway responsiveness. This was accompanied by a reduction of EG2(+) eosinophils (p<0.01), CD3(+) (p<0.001), CD4(+) (p<0.05), CD8(+) (p<0.05) T lymphocytes, and CD25(+)-activated T lymphocytes (p<0.001) in the bronchial mucosa. Significant correlations were found between clinical data and immunohistochemical parameters., Conclusion: These results demonstrated that the beneficial effects ofazelastine in bronchial asthma may result from modulation of local bronchial inflammatory cell infiltration.

Ketotifen is marketed throughout the world as an antiallergy drug, but whether it affects infiltration of inflammatory cells into airway mucosa is not known. We studied the effects of ketotifen on symptoms, pulmonary function, and airway inflammation in 25 patients with atopic asthma. Patients took ketotifen (1 mg twice daily) or a matching placebo for 8 weeks in a double-blind, parallel-group study. Data recorded on diary cards were used for 2 weeks before treatment began, and they were used for the last 2 weeks of treatment to study asthma symptoms, use of beta 2-agonists, and peak expiratory flow (PEF). Pulmonary function tests, bronchial responsiveness to methacholine, and fiberoptic bronchoscopy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. Specimens were stained immunohistochemically with monoclonal antibodies against stored eosinophil cationic protein (EG1), the secreted form of eosinophil cationic protein (EG2), mast-cell tryptase (AA1), neutrophil elastase (NP57), CD3, CD4, CD8, and CD25. The numbers of positively stained cells in the lamina propria were counted. Compared with the placebo, the ketotifen-treated group exhibited significant improvement of asthma symptoms (P < 0.05) and bronchial responsiveness (P < 0.05). This was accompanied by a reduction of EG2+ eosinophils (P < 0.05), CD3+ T cells (P < 0.001), CD4+ T cells (P < 0.01), and CD25+ activated T cells (P < 0.01) in the bronchial mucosa. These results suggested that the beneficial effects of ketotifen in bronchial asthma may result from consequent inhibition of activated eosinophils and T-cell recruitment into the airway. Moreover, ketotifen may relieve allergic inflammation in bronchial asthma.

There is no direct evidence of the anti-inflammatory effect of inhaled sodium cromoglycate (SCG). To investigate whether inhaled SCG has any effect on cellular infiltration into the bronchial mucosa and the expression of adhesion molecules in patients with asthma, biopsies of the bronchial mucosa were taken from nine patients with atopic bronchial asthma before and after treatment with inhaled SCG (8 mg x day(-1)) from a metered-dose inhaler (MDI). Eosinophils were stained with anti-EG2, neutrophils with anti-NP57, mast cells with anti-AA1, T-lymphocytes with anti-CD4, CD8 and CD3, and macrophages with anti-CD68. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1) and P-selectin were stained at the same time as adhesion molecules expressed in vascular endothelium. The intensity of ICAM-1 expression in the bronchial epithelium was also evaluated. The numbers of eosinophils, mast cells, T-lymphocytes and macrophages were significantly reduced as a result of SCG administration, and the expression of ICAM-1, VCAM-1 and ELAM-1 was also significantly inhibited. A significant correlation was found between ICAM-1 expression and T-lymphocytes and between VCAM-1 expression and eosinophils. It was concluded that sodium cromoglycate does have an effect on the infiltration of the bronchial mucosa by inflammatory cells and also on the expression of adhesion molecules.

We biopsied the bronchial mucosa of 20 atopic bronchial asthma patients and measured their serum eosinophil cationic protein (ECP) levels as a means of assessing whether serum ECP could be as a marker of airway eosinophil inflammation. We also investigated the relationship between serum ECP levels and airway hypersensitivity, pulmonary function, peak expiratory flow (PEF) and attack scores. EG2 monoclonal antibody was used to immunostain bronchial mucosal tissue, and positive cells were expressed as the number of positive cells per square millimeter of lamina propria mucosae. A significant correlation was found between bronchial mucosa EG2+ cell counts and serum ECP levels (r = 0.66, p < 0.01), but no clear relationships were detected between serum ECP levels and airway hypersensitivity, pulmonary function, PEF or attack scores. Based on the above findings, serum ECP levels reflect airway eosinophilic inflammation, but ECP levels must be considered in combination with other parameters in relation to the pathophysiology of asthma.

The effects of inhaled beclomethasone dipropionate (BDP) on asthma symptoms and infiltration of the bronchial mucosa by inflammatory cells were investigated in an open study of 10 patients with mild-to-moderate nonatopic bronchial asthma. Asthma scores were recorded in an asthma diary. Peak expiratory flow (PEF), PEF diurnal variation (PEF%), forced expiratory volume in one second (FEV1%), methacholine airway hypersensitivity (minimum dose of methacholine) (Dmin) were measured. Biopsy of the bronchial mucosa was performed before and after 8 weeks of treatment with BDP (400 micrograms.day-1). The following inflammatory cells were immunostained: eosinophils with anti-EG2; mast cells with AA1; neutrophils with NP57; T-lymphocytes with anti-CD3, CD4, and CD8; and activated T-lymphocytes with anti-CD25. There was a significant improvement in the asthma symptom score, PEF%, FEV1%, and Dmin after BDP therapy and the number of EG2-, AA1-, CD3-, CD4-, and CD25-positive cells decreased significantly. We conclude that inhaled beclomethasone dipropionate inhibited inflammatory cell infiltration of airway tissue and that associated with this there was an improvement of symptoms in this open study of inhaled beclomethasone dipropionate in a group of nonatopic asthmatic subjects.

We studied the effect of disodium cromoglycate (DSCG) used as a therapeutic drug for the treatment of bronchial asthma on infiltration of inflammatory cells into the bronchial mucosa and on the expression of adhesion molecules in asthmatic patients. Biopsies of the bronchial mucosa of 9 patients with atopic asthma were performed before and after the administration of an aerosol containing DSCG (8 mg/day). Staining with anti-EG2 antibody was made on the tissues obtained to determine the number of eosinophils, with anti-NP57 antibody to determine the number of neutrophils, with anti-AA1 antibody for mast cells, with anti-CD4, -CD8, -CD3 for T lymphocytes, and with anti-CD68 antibody for macrophages. Another staining was made to examine the expression of adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1) on the vascular endothelium and to determine the presence of P-selection. Moreover, the intensity of the expression of ICAM-1 on the bronchial epithelium was investigated. The number of eosinophils, mast cells, T lymphocytes and macrophages were significantly decreased, and the expression of ICAM-1, VCAM-1 and ELAM-1 were significantly inhibited by the administration of DSCG. There were significant correlations between ICAM-1 and the number of T lymphocytes, and between VCAM-1 and the number of eosinophils. These results suggest that DSCG inhibits the expression of adhesion molecules as an anti-inflammatory action, and decreases the number of inflammatory cells in the airways of asthmatic patients.

Numbers of T lymphocytes, eosinophils, neutrophils, and mast cells in samples of bronchial mucosa were measured with monoclonal antibodies. Samples were obtained by biopsy from atopic (A) and non-atopic (NA) patients with bronchial asthma, and from healthy control subjects (C). The numbers of T lymphocytes, eosinophils, and neutrophils did not differ significantly between the A group and the NA group, but the A group had significantly more mast cells than the NA group (p < 0.025). The difference was greatest in the mucosal epithelium (p < 0.01). Electron microscopy revealed many degranulating mast cells in the A group. These results suggest that in atopic patients with bronchial asthma, mast cells infiltrate into bronchial mucosal epithelium and contribute to inflammation.

It is clear that bronchial asthma is caused by chronic airway inflammation. However, no standard treatment has been developed since opinions regarding the use of anti-allergic agents vary from country to country. I studied the effect of ketotifen, a popular anti-allergic drug, on inflammatory cells in bronchial mucosa. I obtained bronchial mucosa specimens by bronchoscopy from eight atopic asthmatics of mild to moderate severity before and after ketotifen (2 mg/day) treatment and also obtained from 5 normal healthy adults for control study. I used monoclonal antibodies for immunohistochemical staining: anti-EG2 for eosinophils, anti-NP57 for neutrophils, anti-CD3, anti-CD4 and anti-CD8 for T lymphocytes, anti-CD25 and anti-HLA-DR for activated T lymphocytes. I also stained mast cells with toluidine blue. The number of eosinophils, neutrophils, T lymphocytes and activated T lymphocytes in the bronchial mucosa of the asthmatic patients were significantly decreased after treatment with ketotifen. These results suggest that ketotifen decreases the inflammatory cells in the airway, and improves allergic inflammation in bronchial asthma.

Plasma levels of arachidonic acid metabolites, such as thromboxane A2 (TXA2), prostacyclin (PGI2) and leukotrienes (LTS) were measured in patients with exercise-induced asthma (EIA). Asthmatic patients were exercised by treadmill. Before, immediately after and at 5, 15 and 30 minutes after exercise, pulmonary function tests were performed and peripheral venous blood was collected at the indicated times. Plasma TXB2 levels rose after exercise, and this tendency was stronger in EIA negative patients than in EIA positive patients. Plasma 6-keto-PGF1 alpha levels rose slightly after exercise in both EIA positive and negative patients. Plasma LTC4 levels were almost unchanged after exercise in EIA positive patients. Plasma LTC4 levels rose after exercise in EIA negative patients, though the value was always higher in EIA positive patients than in EIA negative patients. Plasma LTB4 levels in both EIA positive and negative patients increased slightly till 5 minutes after exercise, then decreased, and then tended to rise again. Plasma LTB4 levels were higher in EIA positive patients than in EIA negative patients at all times. The ratio of TXB2 to 6-keto-PGF1 alpha after exercise rose more remarkably in EIA negative patients than in EIA positive patients. From these results, we suspected that the metabolites of arachidonic acid may contribute less to chemical mediators of EIA, but the arachidonic acid products of EIA positive patients activated rather towards lipoxygenase cascade than EIA negative patients.