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2.  Longitudinal increase in total IgE levels in patients with adult asthma: an association with poor asthma control 
Respiratory Research  2014;15(1):144.
Immunoglobulin (Ig) E is well-known to play a critical role in allergic diseases. We investigated the association between longitudinal change in total IgE level and the asthma control in patients with adult asthma.
For this retrospective study, 154 patients with asthma aged 21–82 years were recruited from the allergy and pulmonary units of the Showa University Hospital. Data on longitudinal changes in IgE over the preceding 10 years were collected and logarithmically transformed. Associations between longitudinal change in IgE and clinical characteristics including asthma control test (ACT) score, asthma control, pulmonary function test, and antigen specific IgE, were assessed.
Patients with increased IgE tended to have significantly higher mean age, more episodes of acute exacerbation within a year, lower ACT scores, and used oral corticosteroids more frequently than those with decreased or unchanged IgE. The prevalence of uncontrolled asthma was higher in patients with increased IgE than in those with decreased or unchanged IgE. Mean %FEV1 and FEV1% were lower in patients with increased IgE than in those with decreased or unchanged IgE. Moreover, the prevalence of Aspergillus-specific IgE was higher in patients with increased IgE than in those with decreased or unchanged IgE.
These data suggest that a longitudinal increase in total IgE is associated with both poor asthma control and Aspergillus-specific IgE in patients with adult asthma.
PMCID: PMC4245732  PMID: 25409901
IgE; Longitudinal change; Severe asthma; Aspergillus; house dust mite
3.  Pretreatment with inhaled procaterol improves symptoms of dyspnea and quality of life in patients with severe COPD 
The clinical efficacy of short-acting β2-agonists administered before performing daily activities in chronic obstructive pulmonary disease (COPD) is unclear. The aim of this study was to investigate the clinical effect of supplementary inhaled procaterol hydrochloride in patients with COPD.
Thirty outpatients with moderate to severe COPD (Stage II–IV) regularly using inhaled tiotropium bromide alone and with dyspnea during daily activities were enrolled. Subjects self-administered 20 μg of inhaled procaterol before daily activities no more than four times daily. Dyspnea symptom scores, St George’s Respiratory Questionnaire (SGRQ) activity domains, impulse oscillometry system parameters, and pulmonary function tests were recorded at the beginning and end of the 2-week study.
At baseline, more than 80% of subjects reported dyspnea when walking up a slope (100.0%), climbing stairs (100.0%), gardening (93.3%), walking on flat ground (90.0%), bathing (86.7%), getting on a bus or train (83.3%), and changing clothes (80.0%). After 2 weeks, subjects with Stage III symptoms had significantly improved dyspnea scores on walking up a slope (P = 0.047), climbing stairs (P = 0.014), gardening (P = 0.034), walking on flat ground (P = 0.006), getting on a bus or train (P = 0.039), and changing clothes (P = 0.045). Both symptom and activity SGRQ domains improved significantly in subjects with Stage III symptoms (P = 0.036 and P = 0.028, respectively). Resistance of small airways and low-frequency reactance area values improved significantly in subjects with Stage III symptoms (P = 0.003 and P = 0.004, respectively). No significant changes were found in pulmonary function tests.
Use of supplementary inhaled procaterol before performing daily activities improved dyspnea symptoms in subjects with Stage III COPD.
PMCID: PMC3396116  PMID: 22807639
chronic obstructive pulmonary disease; impulse oscillometry system; procaterol; daily activities; quality of life
4.  Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma 
Thymic stromal lymphopoietin (TSLP) triggers dendritic cell–mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)–1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter–reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting β2-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14–1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.
PMCID: PMC3159073  PMID: 20656951
asthma; TSLP; bronchial epithelial cells; combination therapy; genetic polymorphisms
5.  Asthma in Patients With Japanese Cedar Pollinosis 
The World Allergy Organization journal  2012;5(Suppl 3):S218-S222.
Japanese cedar pollen is the most common causative allergen for seasonal allergic rhinitis (AR) in Japan. More commonly known as Japanese cedar pollinosis, it occurs in spring causing the typical symptoms of seasonal AR, such as sneezing, rhinorrhea, nasal obstruction, nasal itching, and itching of the eyes. Previous reports indicate that the prevalence of Japanese cedar pollinosis among Japanese was 26.5%. According to a more recent questionnaire-based survey, the prevalence of Japanese cedar pollinosis in patients with adult asthma might be up to 30% to 50%, suggesting higher rates than that previously reported. Moreover, 30% to 60% of adult asthmatic patients with concomitant pollinosis have exacerbations of their asthma symptoms during the Japanese cedar pollen season. These findings suggest that concomitant Japanese cedar pollinosis may be an aggravating factor in patients with asthma. As with other pollens, such as grass and birch, Japanese cedar pollen was shown to be a trigger factor for worsening asthma. In clinical practice, a number of Japanese patients with asthma are monosensitized to Japanese cedar pollen but not to other antigens. Further studies are needed to elucidate the mechanisms of Japanese cedar pollen in inducing and in exacerbating asthma. The presence of concomitant AR is often associated with the difficulty in asthma control. However, there has been a controversy whether treating concomitant AR by intranasal corticosteroid would produce better asthma-related outcomes in patients with asthma and AR. The effect of treating concomitant cedar pollinosis by intranasal corticosteroids on asthma control in patients with asthma and cedar pollinosis also remains unknown. Certain systemic treatments, such as leukotriene receptor antagonist and anti-IgE monoclonal antibody, are supposed to reduce the symptoms of both asthma and AR in patients with asthma and concomitant AR. In conclusion, Japanese cedar pollinosis is often associated with exacerbations of asthma. Further investigations are expected to elucidate the precise impact and mechanisms of Japanese cedar pollinosis in asthma.
PMCID: PMC3488934  PMID: 23268482
Japanese cedar pollinosis; asthma; allergic rhinitis
6.  Oxaliplatin-Induced Lung Injury with Allergic Reaction 
A 79-year-old man was diagnosed as stage IV colon cancer and treated with a modified FOLFOX6 (mFOLFOX6) regimen. On the 12th cycle, we observed erythema and dyspnea. Radiographs showed ground grass opacities. Blood tests showed elevated levels of eosinophils and immunoglobulin E. We diagnosed this finding as response to drug allergy and administered high-dose methylprednisolone. The treatment was successful and he was discharged. The drug lymphocyte stimulating test against oxaliplatin was positive, indicating a type I and IV allergic reaction due to oxaliplatin. Regimens including oxaliplatin must be carefully monitored and frequent blood tests and chest radiographs are needed.
PMCID: PMC3587561  PMID: 23467619
Oxaliplatin; mFOLFOX6; Drug-induced pneumonia; Drug lymphocyte stimulating test; Immunoglobulin E
7.  Myelosuppression induced by concurrent chemoradiotherapy as a prognostic factor for patients with locally advanced non-small cell lung cancer 
Oncology Letters  2011;2(5):949-955.
The aim of the present study was to assess whether myelosuppression during concurrent chemoradiotherapy is a prognostic factor for patients with locally advanced non‑small cell lung cancer (NSCLC). We retrospectively analyzed 86 patients with NSCLC who received concurrent platinum-based chemoradiotherapy. Patients were classified into two groups (grades 0-2 and 3-4) according to the most severe neutropenia, anemia or thrombocytopenia observed during concurrent chemoradiotherapy, and survival time and progression-free survival (PFS) time were analyzed. Univariate analysis revealed that overall survival time was significantly longer in patients with grade 0-2 anemia than in those with grade 3-4 anemia (p=0.02). Survival time did not differ significantly on the basis of the severity of neutropenia or thrombocytopenia. Although pre-treatment white blood cell count was a further prognostic factor in univariate analysis, multivariate analysis revealed that the only independent prognostic factor for overall survival time was anemia. Disease stage was an independent prognostic factor for PFS (p=0.04), whereas neutropenia, anemia and thrombocytopenia were not. In conclusion, the severity of anemia during concurrent chemoradiotherapy may be a useful prognostic factor in patients with locally advanced NSCLC.
PMCID: PMC3408010  PMID: 22866156
8.  Cooperative Activation of CCL5 Expression by TLR3 and Tumor Necrosis Factor-α or Interferon-γ through Nuclear Factor-κB or STAT-1 in Airway Epithelial Cells 
CCL5/RANTES contributes to prolonged eosinophilic inflammation and asthma exacerbation after a viral infection. We studied the mechanism of CCL5 expression using viral product double-stranded RNA (dsRNA), a ligand of Toll-like receptor 3 (TLR3), and inflammatory cytokines in airway epithelial cells.
The airway epithelial cell line BEAS-2B was used in our in vitro study, and the levels of CCL5 mRNA and CCL5 protein expression were determined using real-time PCR and ELISA. The activity of the CCL5 promoter region and nuclear factor (NF)-κB was assessed by dual luciferase assay using specific luciferase reporter plasmids. We used actinomycin D to assess the stability of mRNA. Phosphorylation of signal transducer and activator of transcription 1 (STAT-1) was analyzed by Western blot.
Synthetic dsRNA up-regulated the expression of CCL5 mRNA and CCL5 protein. Adding TNF-α or IFN-γ to dsRNA further increased the expression of CCL5. The combination of TNF-α and dsRNA cooperatively activated the CCL5 promoter region and the NF-κB-specific reporter. IFN-γ did not activate these reporters. However, it increased the stability of CCL5 mRNA induced by dsRNA. IFN-γ phosphorylated STAT-1, but dsRNA did not. The effects of IFN-γ were not evident in the cells transfected with short interfering RNA for STAT-1.
Cross-talk between TLR3 signaling and inflammatory cytokines regulates the expression of CCL5 in airway epithelial cells. In this mechanism, TNF-α may activate NF-κB, in cooperation with TLR3 signaling. IFN-γ may stabilize CCL5 mRNA up-regulated by TLR3. This mechanism may depend on STAT-1.
PMCID: PMC3202927  PMID: 20523058
Airway epithelial cells; CCL5/RANTES; Nuclear factor-κB; STAT-1; TLR3
9.  Phase II study of S-1, a novel oral fluoropyrimidine, and biweekly administration of docetaxel for previously treated advanced non-small-cell lung cancer 
We examined the safety and efficacy of the combination of S-1 and biweekly docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC).
Patients with previously treated advanced NSCLC were eligible if they had a performance status of 2 or less, were 80 years or younger, and had adequate organ function. Forty-nine patients (38 men and 11 women; median age, 66 years; range 43–79 years) were enrolled. Patients were treated with the combination of 80 mg/m2 per day of S-1 for 14 consecutive days and 35 mg/m2 of docetaxel on days 1 and 15 every 4 weeks.
The overall response rate was 16.3% (95% confidence interval, 7.6–30.5%). The disease-control rate was 49.0% (95% confidence interval, 34.4–63.7%). The median survival time after this treatment was 9 months (range 1–22 months). The median progression-free survival time was 3 months (range 1–11 months). Response rates and survival times did not differ significantly according to the histological type. Grade 3–5 toxicities included neutropenia in 51.0% of patients, thrombocytopenia in 2.0%, anemia in 20.4%, infection in 24.5%, anorexia in 12.2%, diarrhea in 14.3%, nausea in 6.1%, and dehydration in 4.2%. There was 1 treatment-related death due to severe anorexia, stomatitis, diarrhea, and, as consequence, dehydration.
The combination of S-1 and biweekly docetaxel is an acceptable therapeutic option in patients with previously treated advanced NSCLC regardless of the histological type.
PMCID: PMC3064900  PMID: 20556612
S-1; Docetaxel; Second-line chemotherapy; Non-small-cell lung cancer
10.  Effects of Corticosteroids on Osteopontin Expression in a Murine Model of Allergic Asthma 
Osteopontin (OPN) contributes to the development of T helper 1 (Th1)-mediated immunity and Th1-associated diseases. However, the role of OPN in bronchial asthma is unclear. Corticosteroids reduce airway inflammation, as reflected by the low eosinophil and T-cell counts, and the low level of cytokine expression. We investigated OPN production and the inhibitory effects of corticosteroids on OPN production in a murine model of allergic asthma.
BALB/c mice were sensitized by intraperitoneal injections of ovalbumin (OVA) with alum. Some mice received daily injections of dexamethasone (DEX) or phosphate-buffered saline for 1 week. All OVA-challenged mice were exposed to aerosolized 1% OVA for 30 min an hour after these injections. After the OVA challenge, the mice were killed, and bronchoalveolar lavage (BAL) fluid and lung tissue were examined.
The levels of OPN protein in BAL fluid and OPN mRNA in lung tissue increased after OVA challenge. Most OPN-expressing cells were CD11c+ cells and some were T cells. DEX decreased the levels of OPN protein in the BAL fluid, and those of OPN mRNA and OPN protein in lung tissue.
OPN may play an important role in allergic bronchial asthma. Corticosteroids inhibit OPN production in mice with allergic asthma. The beneficial effect of corticosteroids in bronchial asthma is partly due to their inhibitory effects on OPN production.
PMCID: PMC2844795  PMID: 19494498
Osteopontin; Corticosteroid; Mouse; Dendritic cells; CD11c; Bronchial asthma
11.  Differential Regulation of Chemokine Expression by Th1 and Th2 Cytokines and Mechanisms of Eotaxin/CCL-11 Expression in Human Airway Smooth Muscle Cells 
Airway smooth muscle (ASM) cells may contribute to the pathogenesis of asthma including airway inflammation and remodeling. We focused our study on the regulation of chemokine expression by cytokines and analyzed the mechanisms of eotaxin/CCL-11 expression in ASM cells.
Human ASM cells were cultured in vitro and treated with IL-4, interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα). Secretion of chemokines into the culture medium was analyzed by ELISA. Expression of eotaxin mRNA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Binding of transcription factor signal transducer activator of transcription (STAT) 6 to the eotaxin promoter-derived DNA was analyzed by pull-down Western blot. To assess transcriptional regulation of eotaxin, cells were transfected with eotaxin promoter-luciferase reporter plasmids, and activity was determined by dual luciferase assay.
The Th2 cytokine IL-4 preferentially stimulated the expression of the CC chemokine receptor (CCR) 3-ligand chemokines eotaxin, eotaxin-3, and MCP-4. The Th1 cytokine IFNγ stimulated the expression of chemokines IP-10 and RANTES. IL-4 stimulated nuclear translocation of signal transducer activator of transcription 6 (STAT6) and its binding to the eotaxin promoter region. IL-4 activated the eotaxin promoter and its activity was inhibited by mutation of the binding site for STAT6 in the promoter.
The Th2 cytokine IL-4 preferentially stimulated the expression of CCR3 ligand chemokines including eotaxin in ASM cells. The transcription factor STAT6 may play a pivotal role in the activation of eotaxin transcription in response to IL-4.
PMCID: PMC2121189  PMID: 17541284
Interleukin-4; Signal transducer activator of transcription 6; Eotaxin; Smooth muscle cells
12.  Enhanced expression of interferon-inducible protein 10 associated with Th1 profiles of chemokine receptor in autoimmune pulmonary inflammation of MRL/lpr mice 
Arthritis Research & Therapy  2003;6(1):R78-R86.
MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop systemic lupus erythematosus (SLE)-like disease. The natural history of the pulmonary involvement and the underlying mechanism of leukocyte infiltration into the lungs of MRL/lpr mice and SLE patients remains elusive. We aimed to investigate the expression profiles of chemokines and chemokine receptors in the lung of the SLE-prone mouse. We examined the correlation between lung inflammation and expression of IP-10 (interferon-γ-inducible protein 10), a CXC chemokine, and TARC (thymus- and activation-regulated chemokine), a CC chemokine, in MRL/lpr mice, MRL/Mp-+/+ (MRL/+) mice, and C57BL/6 (B6) control mice. The extent of cell infiltration in the lung was assessed histopathologically. Reverse transcriptase PCR showed up-regulation of IP-10 mRNA expression in the lungs (P < 0.05) of MRL/lpr mice, in comparison with MRL/+ or B6 mice. The increase paralleled increased expression of a specific IP-10 receptor, CXCR3, and correlated with the degree of infiltration of mononuclear lymphocytes. In contrast, lung expression of TARC and its specific receptor, CCR4, were suppressed in MRL/lpr mice. Immunohistology showed that macrophage-like cells were the likely source of IP-10. Flow cytometric analyses revealed that the CXCR3-expressing cells were mainly infiltrating CD4 T cells and macrophages, which correlated with the degree of mononuclear lymphocyte infiltration. Recent data suggest that Th1 cells and Th1-derived cytokines play an important role in the development of SLE-like disease in MRL/lpr mice. Our results suggest that IP-10 expression in the lung is involved, through CXCR3, in the pathogenesis of pulmonary inflammation associated with migration of Th1 cells.
PMCID: PMC400420  PMID: 14979941
autoimmune disease; interferon-γ-inducible protein 10; Th1/Th2; CCR4; CXCR3
13.  A novel mechanism for the regulation of IFN-γ inducible protein-10 expression in rheumatoid arthritis 
Arthritis Research & Therapy  2003;5(2):R74-R81.
Chemokines play an essential role in the progression of rheumatoid arthritis (RA). In the present study we examined the expression and regulatory mechanisms of IFN-γ inducible protein (IP)-10 in RA synovitis. RA synovial fluid contained greater amounts of IP-10 than did synovial fluid from patients with osteoarthritis. Immunolocalization analysis indicated that IP-10 was associated mainly with infiltrating macrophage-like cells, and fibroblast-like cells in the RA synovium. The interaction of activated leukocytes with fibroblast-like synoviocytes resulted in marked increases in IP-10 expression and secretion. Moreover, induction of IP-10 was mediated via specific adhesion molecules, as indicated by the finding that both anti-integrin (CD11b and CD18) and intercellular adhesion molecule-1 antibodies significantly inhibited IP-10 induction. These results suggest that IP-10 expression within inflamed joints appears to be regulated not only by inflammatory cytokines but also by the physical interaction of activated leukocytes with fibroblast-like synoviocytes, and that IP-10 may contribute to the recruitment of specific subpopulations of T cells (Th1 type) from the bloodstream into the synovial joints.
PMCID: PMC165028  PMID: 12718750
adhesion molecule; fibroblast; IFN-γ inducible protein-10; rheumatoid arthritis

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