IL-33 and RANTES( Regulated on Activation, Normal T Cell Expressed and Secreted) in BAL Fluid in Asthma Patients Without Cigarette Smoking

Background:Inflammatory cytokines and chemokines have been reported to play important roles in thepathogenesis of bronchial asthma. However, no criteria for the classification of `smoker\u27 and `atopic\u27 in bronchialasthma have been defined. In this study, we compared the levels of several cytokines found in thebronchoalveolar lavage( BAL) fluid of patients classified as having bronchial asthma.Methods:Cell subpopulations in BAL fluid were counted. BAL fluid levels of interleukin( IL)-4, -5, -13,-17, and -33 and RANTES (regulated on activation, normal T cell expressed and secreted were measuredusing a bead suspension array in 36 asthma patients (13 males, 23 females;mean age, 39.5±92.8 years)who were non-smokers, 18 asthma patients( 11 males, 7 females;mean age, 30.7±2.7 years) who were exor current smokers( Brinkman index( BI):1&#8722;399), and 10 asthma patients( 9 males, 1 female;mean age,50.2±5.5 years) who were current heavy smokers( BI:&#8805; 400). Relationships were assessed by Spearman\u27srank correlation analysis.Results:The number of lymphocytes in BAL cell subpopulations of non-smokers( 25±7×103/ml) weresignificantly (p<0.05) higher than those of heavy smokers (12±3×103 /ml). The number of neutrophilswas significantly( p<0.05) higher in heavy smokers( 18±9×103/ml) than in non-smokers( 4±2×103/ml).Levels of IL-33 and RANTES were significantly (P<0.05) higher in non-smokers (26.1±7.3 pg/ml and42.8±10.3 pg/ml, respectively) than in heavy smokers (13.7±4.5 pg/ml and 27.4±5.4 pg/ml, respectively).In addition, the levels of IL-33 and RANTES in non-smokers were significantly( P<0.05) higher in atopicasthma patients (33.0±9.8 pg/ml and 47.8±14.0 pg/ml, respectively) than in non-atopic asthma patients(9.1±3.8 pg/ml and 29.5±7.8 pg/ml, respectively). A good correlation was noted between RANTES andlymphocytes (R=0.365, P<0.05) or IL-33 (R=0.561, P<0.05) in atopic asthma patients who were nonsmokers.Conclusions:Differences in the cell types of BAL fluid, as well as in the levels of IL-33 and RANTES inasthma patients with or without smoking, might reflect pathogenesis

Mechanism of Airway Remodeling Induced by Repeated Inhalation of Methacholine in a Mouse Model of Asthma

Background:Increased severity of asthma is contributed by airway tissue remodeling, which may be associated with chronic allergic inflammation. A recent study revealed the potential capacity of repeated bronchoconstriction, e.g. induced by a muscarine agonist, methacholine(Mch)challenge, to involve in airway remodeling, even though allergic inflammation is not implicated. We have evaluated the influence of repeated bronchoconstriction induced by Mch inhalation on airway remodeling in a murine model of asthma and have examined its machanisms. Methods:Mice were immunized with ovalbumin(OVA), and consequently, challenged by either daily OVA inhalation(the OVA group;a model of asthma with allergic inflammation)or daily Mch inhalation(the Mch group;a model of asthma without allergic inflammation). Lung tissues were obtained and were evaluated histologically after 5, 10, and 15 consecutive inhalation challenges of both OVA and Mch.Results:Eosinophilia in the airway observed only on the OVA group. Subepithelial collagen-band thickness increased also in the OVA group(p<0.01)after 15 challenges, but not in the Mch group. Significant increase in thickness of airway smooth muscle layer and the number of goblet cells were revealed in both the OVA and Mch group after 10(p<0.05 and p<0.01, p<0.01 and p<0.05, respectively, for the comparison of the two challenge groups with the control group)and 15 challenges(p<0.05 and p<0.01, both p< 0.01, respectively, for the comparison with control), further, all these measurements were greater in the OVA group than in the Mch group after both 10 and 15 challenges(both p<0.05 and p<0.01, respectively). An increase in mast cell counts within the airway wall was shown in the OVA group after 10 challenges (p<0.01 compared with control), not in the Mch group at all. Epithelia expression of transforming growthfactor b (TGF-b)increased in both challenge groups after 15 challenges(both p<0.05 compared with control), and was higher than in Mch(p<0.05).Conclusion:Repeated Mch inhalation may induce airway remodeling, while comparatively mild, potentially resulting in progressive severity of asthma. The results implicate that the potential risk associated with Mch challenge should be considered

Effect of Oral Procaterol in Combination with Inhaled Corticosteroids in Adult Patients with Bronchial Asthma

Background:Bronchial asthma is considered to be a chronic airway inflammatory disease, and inhaledcorticosteroids play a central role in controlling airway inflammation. In some patients, however, it is difficultto control symptoms despite the use of moderate to high doses of inhaled corticosteroids. Long-actinginhaled b2-agonists have recently become available and reconsidered as a controller.Objectives:To examine whether combination of an inhaled corticosteroid and an oral b2-agonist can improvesymptoms in patients with moderate bronchial asthma whose airway obstructive symptoms cannotbe relieved sufficiently by inhaled corticosteroids alone.Methods:Of outpatients in our hospital with moderate bronchial asthma (step 3) given beclomethasoneat a daily dose of 800 mg, whose peak expiratory flow rate in the early morning was 70 % or less of the predictedvalue, 12 patients were enrolled in the study who showed at least 12.5 % improvement in the forcedexpiratory volume in one second (FEV1.0) after inhalation of 20 mg procaterol (Meptin Air from OtsukaPharma. Co.) for 15 minutes. Procaterol tablets (Meptin tablets, 50 mg from Otsuka Pharma. Co.) were administeredin the morning and before bed for 4 weeks, and change in the peak expiratory flow rate, subjectivesymptoms, respiratory function, and the number of puffs of the b2-agonist were evaluated.Results:The peak expiratory flow rate, FEV1.0, forced vital capacity (% FVC),and airway hyperresponsivenessimproved after coadministration of oral procaterol and beclomethasone.Conclusions:The oral b2-agonist in combination with an inhaled corticosteroid might improve asthmasymptoms better than inhaled corticosteroids alone

Involvement of Bird-related IgG Antibodies in Interstitial Pneumonia

Background and Objective:Chronic interstitial pneumonia (IP) might include chronic hypersensitivity pneumonitis (HP) and chronic bird-related hypersensitivity pneumonitis (BRHP). A specific antigen is difficult to identify in these diseases, and such evidence would provide important clues suggesting a diagnosis of HP. In this study, we used an ImmunoCAP analysis system to measure specific IgG antibodies against pigeons and budgerigars in the sera of patients with IP and investigated the involvement of bird-related IgG antibodies in IP.Methods:The study group comprised 22 patients with idiopathic pulmonary fibrosis (IPF), 8 with chronic IP, 7 with subacute HP, 7 with chronic HP, and 10 with control diseases. All cases were diagnosed from 2000 through 2011 at the Institute of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University. Clinical features, results of laboratory examinations, and levels of serum IgG antibodies against pigeons and budgerigars were compared.Results:There were no significant differences among the disease groups in C-reactive protein, leukocyte count, lactate dehydrogenase, and the results of blood gas analysis. KL-6 and surfactant protein D were significantly higher in subacute HP and chronic HP. The levels of anti-pigeon IgG antibodies and anti-budgerigar IgG antibodies in each disease group were respectively as follows:IPF, 11.02±5.97&#8200;mg/l, 5.03±3.97&#8200;mg/l;chronic IP, 10.04±8.55&#8200;mg/l, 3.30±1.47&#8200;mg/l;subacute HP, 14.39±9.13&#8200;mg/l, 7.96±6.47&#8200;mg/l;chronic HP, 24.97±16.19&#8200;mg/l, 11.50±13.80&#8200;mg/l;and control diseases, 8.66±3.15&#8200;mg/l, 3.77±1.05&#8200;mg/l. The mean levels of anti-pigeon IgG antibodies and anti-budgerigar IgG antibodies were significantly higher in chronic HP. There was a positive correlation between anti-pigeon IgG antibodies and anti-budgerigar IgG antibodies (R2 = 0.715, p<0.001). Conclusions:In patients with clinically diagnosed chronic HP, high levels of anti-pigeon IgG antibodies or anti-budgerigar IgG antibodies were confirmed using an ImmunoCAP analysis system. In general, HP (especially chronic HP) is difficult to diagnose definitively, and this analysis system is expected to facilitate diagnosis

Clinical Characteristics of Acute Exacerbations of Idiopathic Pulmonary Fibrosis and Involvement of Viral, Mycoplasma pneumoniae, and Chlamydophila pneumoniae Infections

Background and Objective:To clarify the clinical characteristics of acute exacerbation of idiopathic pulmonaryfibrosis (IPF) and the involvement of infections with pathogenic microorganisms and viruses inacute exacerbation.Methods:During the 12 years from 2000 through 2011, we studied 50 patients who were admitted andreceived treatment for acute exacerbation of IPF in our department. Demographic characteristics, imagingfindings, laboratory findings, changes in antibody titers against bacteria, Mycoplasma pneumoniae, Chlamydophilapneumoniae, and known viruses, and outcomes were studied.Results:Among the 50 patients with acute exacerbation of IPF( 41 men and 9 women) 29 patients died(mortality rate, 58.0%). Computed tomography showed subpleural peripheral ground-glass opacities( GGO)in 5 patients, multiple patchy GGO in 19, and diffuse GGO in 26. Only the PaO2/FiO2 ratio was significantlylower in the non-survivors compared with survivors. Three patients had high titers of IgM antibodiesagainst C. pneumoniae, but acute infection was ruled out by the changes in IgA and IgG antibodies in pairedserum samples. Antibody titers against known viruses significantly increased in 2 patients( respiratory syncytialvirus in 1 and adenovirus 11 in 1). In acute-phase serum samples, 7 patients had increased antibodytiters against parainfluenza virus 3, resulted in no significant change in paired serum samples.Conclusions:Our results suggest that known pathogens do not play a role in acute exacerbation of IPF.The outcomes of IPF remain poor, and the elucidation of the causes and pathological features of acute exacerbationof IPF, including the identification of unknown pathogens, is awaited

Clinical Significance of Propionibacterium acnes in the Formation of Noncaseating Epithelioid-Cell Granulomas of the Mediastinal Lymph Nodes and Lung in Patients with Lung Cancer:Differential Diagnosis Between Sarcoid Reactions and Sarcoidosis

Objectives:Sarcoidosis is a systemic noncaseating epithelioid-cell granulomatous disease of unknown origin.Granulomas occurring around malignant tumors and regional lymph nodes can be caused by sarcoid reactions.The mechanisms underlying sarcoidosis and sarcoid reactions remain unclear. Whether increaseduptake of fluorodeoxyglucose( FDG) in lymph nodes on positron emission tomography( PET) is caused bytumor metastasis, the concurrent presence of sarcoidosis, or sarcoid reactions must be determined to ensureproper disease staging and selection of treatment policy. We studied patients who underwent surgery forlung cancer and had no histopathological evidence of lymph-node metastasis in whom concurrent sarcoidosisor sarcoid reactions were diagnosed.Methods:In six patients who underwent surgery for primary lung cancer, granulomatous lesions werehistopathologically studied in dissected lymph nodes and lung. Tissue sections were stained with monoclonalantibodies against Propionibacterium acnes( PAB antibodies).Results:The six patients had noncaseating epithelioid-cell granulomas in mediastinal lymph nodes andlung. Clinically, concurrent sarcoidosis was suspected, but the results of staining the tissue specimens withPAB antibodies( in granulomas, alveolar macrophages, Hamazaki-Wesenberg bodies, and lymphatic sinuses)suggested sarcoid reactions in 5 patients. In one patient in whom granulomas stained positive with PAB antibodies,concurrent sarcoidosis was diagnosed.Conclusions:In patients with lung cancer who have no distinct systemic evidence of sarcoidosis, thepresence of noncaseating epithelioid-cell granulomas in the lung hilum or mediastinum is usually caused bysarcoid reactions

Antigen Challenge-induced Expression of Amphiregulin by Mast Cells Increases Goblet-Cell Hyperplasia in a Mouse Model of Asthma

Mast cells play important roles in both acute-and late-phase allergic reactions mediated by IgE, such as those in bronchial asthma. Remodeling of the airway wall may contribute to the development of chronic refractory asthma; effective treatment for remodeling is currently lacking. Tryptase released by degranulated mast cells may participate in airway remodeling by stimulating the proliferation of airway smooth-muscle cells and fibroblasts and promoting the production of extracellular matrix. We found that continued antigen challenge produced time-dependent increases in the number of goblet cells, which are essential for sputum production, as well as the number of mast cells. Furthermore, the expression of amphiregulin released from mast cells was up-regulated by after ovalbumin challenges in mice. The number of amphiregulin-positive cells positively correlated with the degree of goblet-cell hyperplasia. Our results suggest that mast cells also play a key role in airway remodeling

Analysis of the Characteristics of Patients Presenting with Exacerbation of Asthma to Emergency Care Units

Background:Fatal asthma remains a serious problem, and patient self-management of asthma is important to prevent exacerbation. To reduce the asthma mortality rate, we analyzed the characteristics of patients who visited an emergency care unit with exacerbation of asthma.Methods:Subjects were 317 patients(135 men, 182 women;mean age, 47.0 years)who visited the emergency room at Dokkyo Medical University Hospital or Dokkyo Medical University Koshigaya Hospital for exacerbation of asthma between April 2010 and March 2011. When categorized by severity, 41.3% ofpatients were step 1, 8.2% were step 2, 18.9% were step 3, 30.9% were step 4, and 0.6% were unknown. When categorized by primary care physician, 60.3% of patients had a primary care physician at Dokkyo Medical University, 13.6% had one at another hospital, and 26.2% had no primary care physician. When categorized by recovery from exacerbation, control was achieved within 1 day in 63.1% of cases, after more than 1 day in 30.6% of cases, and required admission in 6.3% of cases.Results:The rate of admissions was highest for cases with step 1 severity(step 1, 55.0%;step 2, 20.0%;step 3, 0.0%;and step 4, 25.0%). The rate of admissions did not differ significantly by age(age 15-39 years, 40.0%;40-65 years, 25.0%;>65 years, 35.0%). Initial value of oxyhemoglobin saturation(SpO_2) measured by pulse oximetry was significantly lower in the admission group(SpO_2 92.4%)than in the nonadmissiongroup(SpO_2 95.2%, p<0.01).Conclusion:Patients with step 1 severity who visit an emergency unit with exacerbation of asthma may need regular treatment for asthma. When initial SpO_2 is less than 92%, we should consider hospitalization for treatment of asthma

A Case of Pulmonary Benign Metastasizing Leiomyoma Occurring after Uterine Myomectomy

Benign metastasizing leiomyoma (BML) is a very rare disease, and although it was reported as early as1939 to result from metastasis of benign uterine myoma to the lungs and lymph nodes, its pathology remainsobscure. Here, we describe a case of pulmonary BML occurring after uterine myomectomy in a42-year-old woman. She presented with a 2-week history of dry cough on exertion. Chest radiography andcomputed tomography( CT) revealed bilateral multiple nodular lesions. The patient had a history of uterinemyoma and previously underwent myomectomy. For definitive diagnosis, lung biopsy was performed byvideo associated thoracoscopic surgery. Histopathologic examination of biopsy specimens revealed pulmonaryBML occurring after uterine myomectomy. For treatment of the pulmonary BML, gonadotropin-releasinghormone was initially administered, and 1 month later the patient underwent complete hysterectomyand bilateral salpingo-oophorectomy. Chest CT 6 months after surgery showed that the size and number oflung multiple nodular lesions did not increase compared with those before surgery. In future studies, we aimto investigate a larger number of pulmonary BML cases, as well as establish specific treatments and investigatethe prognosis of the disease.Abbreviations:BML:benign metastasizing leiomyomaSS:Sj&ouml;gren\u27s syndromeCT:computed tomographyH&E:hematoxylin and eosinVATS:video associated thoracoscopic surgeryCA:carbohydrate antigenIg:immunoguloblina SMA:a smooth muscle acti

Exogenous S100A4 Protein Attenuates Bleomycin-induced Pulmonary Fibrosis in Mice by Reducing the Levels of Fibroblast Growth Factors

Background and objective:The calcium-binding protein S100A4 belongs to the S100 family and is involved in fibrotic and inflammatory processes, in which tissue remodeling, cell motility, and epithelialmesenchymal transition play major roles. Cytoplasmic S100A4 is a marker of lung fibroblasts in pulmonary fibrosis;however, the effects of exogenous S100A4 on fibrotic and inflammatory processes in pulmonary fibrosis are unclear. This study examined the effects of exogenous S100A4 protein in mice with bleomycin-induced pulmonary fibrosis.Methods:Bleomycin was administered to mice by intratracheal instillation on day 1. Intratracheal S100A4 protein was administered 4 times after bleomycin treatment. Bronchoalveolar lavage fluid was obtained and lung histological examinations were performed on day 14 after bleomycin administration. Lung tissue was homogenized on the same day to assess the mRNA expression of cytokines, fibroblast growth factors, and S100A4.Results:Unexpectedly, we observed that the administration of exogenous S100A4 protein apparently reduced lung fibrosis in bleomycin-treated mice. In addition, the levels of lymphocyte accumulation and insulin-like growth factor-1 mRNA were significantly reduced in bleomycin-treated lung by S100A4 administration.Conclusions:Exogenous S100A4 protein attenuates bleomycin-induced pulmonary fibrosis in mice by reducing lymphocyte function and the levels of fibroblast growth factors