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ABSTRACT: BACKGROUND: Combination therapy with an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABA) in a single inhaler is the mainstay of asthma management. We previously showed that switching from salmeterol/fluticasone combination (SFC) 50/250 μg bid to a fixed-dose formoterol/budesonide combination (FBC) 9/320 μg bid improved asthma control and pulmonary functions, but not fractional exhaled nitric oxide (FeNO), in patients with asthma not adequately controlled under the former treatment regimen. OBJECTIVE: To assess whether switching from SFC to FBC improves peripheral airway/alveolar inflammation in asthma (UMIN000009619). METHODS: Subjects included 66 patients with mild to moderate asthma receiving SFC 50/250 μg bid for more than 8 weeks. Patients were randomized into FBC 9/320 μg bid or continued the same dose of SFC for 12 weeks. Asthma Control Questionnaire, 5-item version (ACQ5) score, peak expiratory flow, spirometry, FeNO, alveolar NO concentration (CANO), and maximal NO flux in the conductive airways (J'awNO) were measured. RESULTS: Sixty-one patients completed the study. The proportion of patients with an improvement in ACQ5 was significantly higher in the FBC group than in the SFC group (51.6% vs 16.7%, respectively, p = 0.003). A significant decrease in CANO was observed in the FBC group (from 8.8 ± 9.2 ppb to 4.0 ± 2.6 ppb; p = 0.007) compared to the SFC group (from 7.4 ± 7.8 ppb to 6.4 ± 5.0 ppb; p = 0.266) although there was no significant difference in the changes in pulmonary functions between the 2 groups. Similar significant differences were found in the CANO corrected for the axial back diffusion of NO (FBC, from 6.5 ± 8.2 ppb to 2.3 ± 2.5 ppb; and SFC, from 4.3 ± 5.3 ppb to 3.9 ± 4.3 ppb). There was no difference in the changes in FeNO or J'awNO between the 2 groups. CONCLUSIONS: Switching therapy from SFC to FBC improves asthma control and peripheral airway/alveolar inflammation even though there is no improvement in pulmonary functions, and FeNO in asthmatic patients.
Pulmonary Pharmacology & Therapeutics 04/2013; · 2.80 Impact Factor
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ABSTRACT: BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three-dimensional MDCT. METHODS: Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD. RESULTS: The median age was 73.5 years and the mean forced expiratory volume in 1 second (FEV(1)) as a percentage of the predicted value was 57.2 ± 18.3 %. The luminal area in the fifth generation bronchi and the emphysema volume/CT-derived total lung volume were significantly correlated with FEV(1) at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 ± 9.7 to 26.0 ± 9.9 mm(2) in the third generation, 13.0 ± 6.5 to 14.7 ± 7.3 mm(2) in the fourth generation, 8.0 ± 4.8 to 9.4 ± 4.9 mm(2) in the fifth generation and 5.6 ± 2.7 to 6.7 ± 3.6 mm(2) in the sixth generation (p<0.01). The average increase of the third generation luminal area was correlated with the FEV(1) increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 ± 9.2 to 49.1 ± 9.7 in the third generation, 56.1 ± 9.7 to 53.0 ± 11.1 in the fourth generation, and 62.3 ± 9.9 to 57.6 ± 9.8 in the fifth generation (p<0.05). Emphysema volume/CT-derived total lung volume was unchanged with treatment. CONCLUSION: MDCT demonstrated budesonide/formoterol-induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD.
Pulmonary Pharmacology & Therapeutics 01/2013; · 2.80 Impact Factor
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ABSTRACT: BACKGROUND AND OBJECTIVE: Increased fraction of exhaled nitric oxide (FeNO) has been shown to reflect airway inflammation in asthma. Central airway NO flux (J'awNO; nl/s) and peripheral airway/alveolar NO concentration (CANO; ppb) can be calculated separately. CANO has been reported to reflect small airway inflammation. The aim of the present study is to correlate CANO levels with clinical and physiological parameters in patients with stable asthma. METHODS: Seventy-three well-controlled asthmatics (mean age 61) were enrolled. Measurement of FeNO (at 50, 100, 150, and 200 ml/s) and pulmonary function test were performed. J'awNO(TMAD) and CANO(TMAD) were calculated and corrected by the trumpet shape of the airway tree and axial back-diffusion (TMAD). RESULTS: CANO(TMAD) was significantly correlated with FEF(25-75) , FEF(25-75) %pred, FEF(50,) FEF(50) %pred (R = -0.39 p = 0.002, R = -0.29 p = 0.02, R = -0.39 p = 0.001, R = -0.29 p = 0.02, respectively). CANO(TMAD) was positively correlated with age (R = -0.45 p = 0.0002), and weakly correlated with duration of asthma (R = -0.27 p = 0.03). FEV(1) /FVC was negatively correlated with CANO(TMAD) , J'awNO(TMAD) and FeNO 50ml/s. Among these, correlation between FEV1/FVC and FeNO 50ml/s was the strongest (R = -0.34 p = 0.004). CONCLUSIONS: CANO(TMAD) may be a more specific marker of peripheral airway obstruction than FeNO and J'awNO(TMAD) in stable asthma.
Respirology 12/2012; · 2.42 Impact Factor
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Hideki Kusagaya,
Yutaro Nakamura,
Masato Kono,
Yusuke Kaida,
Shigeki Kuroishi,
Noriyuki Enomoto,
Tomoyuki Fujisawa,
Naoki Koshimizu,
Koshi Yokomura, Naoki Inui,
Takafumi Suda,
Thomas V Colby,
Kingo Chida
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ABSTRACT: BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recently reported group of disorders characterized by fibrotic thickening of the pleural and subpleural parenchyma predominantly in the upper lobes. We report five Japanese cases fulfilling the criteria of IPPFE and address whether it should be considered a separate clinicopathologic entity. And this study was an attempt to identify features in common between IPPFE and previously described idiopathic upper lobe fibrosis (IPUF), allowing IPPFE to be considered as a distinct entity in our Japanese series. METHODS: Five consecutive cases of idiopathic interstitial lung disease confirmed as IPPFE by surgical lung biopsy were studied. RESULTS: There were four males and one female, aged 70+/-2.76 yr. No associated disorder or presumed cause was found in any case. Lung function tests found a restrictive ventilatory defect (4/5) and/or impairment of DLco (4/5). Chest X-ray showed marked apical pleural thickening in all cases. Computed tomography of the chest in all cases mainly showed intense pleural thickening and volume loss associated with evidence of fibrosis, predominantly in the upper lobes. In all cases in this study, markedly thickened visceral pleura and prominent subpleural fibrosis characterized by both elastic tissue and dense collagen were clearly shown. All cases were alive at the last follow-up, 17.6+/-13.59 months after diagnosis; however, all had deteriorated both clinically and radiologically. CONCLUSIONS: IPPFE deserves to be defined as a separate, original clinicopathologic entity owing to its uniformity and IPPFE has some features in common with previously described idiopathic upper lobe fibrosis (IPUF). Our limited experience with a cohort of 5 subjects suggests that IPPFE can be rapidly progressive.
BMC Pulmonary Medicine 12/2012; 12(1):72. · 1.33 Impact Factor
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ABSTRACT: Transdermal absorption of morphine into the systemic circulation through intact skin has not been reported.
To describe a novel transdermal formulation for a morphine hydrochloride patch consisting of polyethylene sponge foam as the retaining agent and adjusted proportions of morphine hydrochloride and adjunctive drugs.
In this study, the transdermal morphine hydrochloride patch was administered to intact skin in five subjects and the plasma concentrations of morphine and its metabolites were examined.
Morphine was absorbed systemically, producing plasma morphine concentrations above the assay detection limit by at least 24 hours after attachment of patches containing a total dose of 180mg of morphine. The levels gradually increased in a time-dependent manner without serious events. The area under the concentration-time curve from 0 to 72 hours (AUC(0-72)) values for morphine, morphine-6-glucuronide, and morphine-3-glucuronide were 60.4±13.4, 133.7±17.4, and 861.5±126.7ng·h/mL, respectively. The mean plasma area under the concentration-time curve from 0 to 72 hours ratio for morphine-6-glucuronide relative to morphine was 2.64.
These data provide useful information for developing a transdermal morphine system.
Journal of pain and symptom management 06/2012; 44(4):479-85. · 2.42 Impact Factor
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Hideki Kusagaya, Naoki Inui,
Masato Karayama,
Yutaro Nakamura,
Shigeki Kuroishi,
Koshi Yokomura,
Mikio Toyoshima,
Toshihiro Shirai,
Masafumi Masuda,
Takashi Yamada,
Kazumasa Yasuda,
Takafumi Suda,
Kingo Chida
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ABSTRACT: The strategy of chemotherapy in the elderly is controversial. We wanted to evaluate the efficacy and safety of biweekly gemcitabine and low-dose carboplatin combination therapy in elderly patients with advanced non-small-cell lung cancer (NSCLC).
In this phase-II trial, chemotherapy-naive elderly patients (aged ≥76 years) with NSCLC were randomly treated with biweekly combination therapy with gemcitabine and carboplatin (1000 mg/m(2) gemcitabine and carboplatin at an area under the curve (AUC) of 3 on days 1 and 15, every 4 weeks) or gemcitabine monotherapy (1000 mg/m(2) on days 1, 8 and 15, every 4 weeks). The primary endpoint was overall response rate and analysis was based on intention-to-treat.
Thirty-one patients were randomly assigned combination therapy and 30 were assigned monotherapy. The median age was 79.0 years. Response rate was 22.6% (95% confidence interval (CI): 11.4-39.8%) for biweekly combination therapy and 10.0% (95% CI: 3.5-25.6%) for monotherapy. Median progression-free survival in combination chemotherapy was 3.9 months (95% CI: 0.5-8.5 months), which was significantly longer that that in monotherapy (2.4 months, 95% CI: 0.5-6.7 months). The prevalence of hematological and non-hematological adverse events reaching grade 3/4 was not significantly different between combination therapy and monotherapy.
Biweekly gemcitabine and low-dose carboplatin combination chemotherapy showed acceptable efficacy, toxicity, and tolerability in those aged ≥76 years with NSCLC. Further investigations with a large population are required to confirm our results.
Lung cancer (Amsterdam, Netherlands) 06/2012; 77(3):550-5. · 3.14 Impact Factor
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Yutaro Nakamura,
Takafumi Suda,
Yusuke Kaida,
Masato Kono,
Hironao Hozumi,
Dai Hashimoto,
Noriyuki Enomoto,
Tomoyuki Fujisawa, Naoki Inui,
Shiro Imokawa,
Kazumasa Yasuda,
Toshihiro Shirai,
Hideki Suganuma,
Satoru Morita,
Hiroshi Hayakawa,
Yasuo Takehara,
Thomas V Colby,
Kingo Chida
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ABSTRACT: To investigate the prognostic significance of histopathological characteristics in patients with biopsy-proven rheumatoid lung disease (RLD).
Retrospective analysis was conducted on samples from 54 RLD patients who underwent surgical lung biopsies (SLBs) at Hamamatsu University Hospital and affiliated hospitals between 1980 and 2009. The overall survival rate, the spectrum of histopathological diagnosis and their associated prognostic significance were investigated.
The study group consisted of 30 men and 24 women with a median age of 60.3 years. Histopathological analysis revealed the following: usual interstitial pneumonia (UIP), 15 cases; nonspecific interstitial pneumonia/fibrosis, 16 cases; organizing pneumonia, 4 cases; unclassifiable, 2 cases; desquamative interstitial pneumonia, 1 case; and bronchiolar disease, 16 cases. In survival outcome, 10 yr survival rate was 76.6%. Patients with UIP had significantly worse prognosis than those with non-UIP (RLD cases except those with UIP) (p = 0.0452).
RLD includes several histopathological groups. Patients with UIP have worse survival than those with other types of RLD. Histopathological diagnosis may have a major impact on prognostication in patients with RLD.
Respiratory medicine 05/2012; 106(8):1164-9. · 2.33 Impact Factor
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Hideki Yasui,
Tomoyuki Fujisawa, Naoki Inui,
Masato Kato,
Dai Hashimoto,
Noriyuki Enomoto,
Yutaro Nakamura,
Toshihiro Shirai,
Takafumi Suda,
Hirotoshi Nakamura,
Kingo Chida
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ABSTRACT: BACKGOUND: The importance of airway inflammation has been highlighted in the pathophysiology of asthma. Even in controlled asthmatics treated with inhaled corticosteroid (ICS), residual airway inflammation is reported. Systemic therapy with oral leukotriene receptor antagonist, pranlukast, may have additive effects to improve asthma control.
Twenty-five controlled asthmatics treated with ICS or ICS plus long-acting β2-agonist (LABA) were enrolled for a randomized crossover trial evaluating the effect of additional oral pranlukast. The patients were assigned to two groups receiving ICS (+LABA) or ICS (+LABA) + pranlukast for 8 weeks. After washout period, two groups were switched over for another 8 weeks. Fraction of exhaled nitric oxide (FeNO), lung function tests, peak expiratory flow (PEF) and asthma control test (ACT) were evaluated at the beginning and end of each period. Central airway NO flux (J'(awNO)) and peripheral airway/alveolar NO concentration (C(ANO)) were measured and adjusted for axial NO back-diffusion.
FEV1, % predicted, forced expired flow (FEF) (25-75), % predicted, morning PEF and ACT were significantly increased after the addition of pranlukast. Oral pranlukast administration significantly decreased both C(ANO) and corrected C(ANO).
The addition of oral pranlukast to ICS or ICS + LABA therapy may improve asthma control with reducing distal airway inflammation. Trial registration: UMIN 000003781.
Respiratory medicine 04/2012; 106(4):508-14. · 2.33 Impact Factor
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ABSTRACT: Multidrug resistance protein 1 and multidrug resistance-associated protein 1 are transporters that efflux diverse xenobiotics from cells. We investigated changes in the expression and activity of multidrug resistance protein 1 and multidrug resistance-associated protein 1 in highly purified lung dendritic cells (LDCs) during aging using magnetic and flow cytometric cell sorting. Multidrug resistance protein 1 blockade by the specific inhibitor reduced the percentage of rhodamine 123(low) cells in LDCs from aged mice (54.8% ± 2.6% to 13.2% ± 2.5%, p < .01). The difference in the proportions of rhodamine 123(low) cells in aged LDCs was more apparent than that in LDCs from young mice (p < .05). The multidrug resistance-associated protein 1-specific inhibitor reduced the percentage of Fluo-3(low) cells in aged LDCs (60.8% ± 5.3% to 25.8% ± 7.5%, p < .01). The difference in the proportions of Fluo-3(low) cells in aged LDCs was smaller than that in young LDCs (p < .05). These data showed that LDCs from aged mice exhibited multidrug resistance protein 1- and multidrug resistance-associated protein 1-mediated efflux and that the age-associated changes differed according to transporters.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 03/2012; 67(10):1049-55. · 4.60 Impact Factor
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Taisuke Akamatsu,
Toshihiro Shirai,
Masato Kato,
Dai Hashimoto,
Hideki Yasui, Naoki Inui,
Takafumi Suda,
Koshi Yokomura,
Hiroshi Hayakawa,
Kyotaro Ide,
Mikio Toyoshima,
Shigeki Kuroishi,
Kazumasa Yasuda,
Hideki Suganuma,
Takashi Yamada,
Masafumi Masuda,
Kingo Chida
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ABSTRACT: Combination therapy with an inhaled corticosteroid (ICS) and a long-acting β(2)-agonist (LABA) in a single inhaler is the mainstay of asthma management and salmeterol/fluticasone combination (SFC) and fixed-dose formoterol/budesonide combination (FBC) are currently available in Japan; however, there is nothing to choose between the two. The purpose of this study was to clarify the effect of switching from SFC to FBC in patients with asthma not adequately controlled under the former treatment regimen.
This was a prospective, multicenter, open-label, uncontrolled longitudinal study in 87 adult patients with an Asthma Control Questionnaire, 5-item version (ACQ5) score of greater than 0.75 under treatment with SFC 50/250μg one inhalation twice daily (bid). SFC was switched to FBC 4.5/160μg two inhalations bid. Study outcomes included ACQ5 score, peak expiratory flow (PEF), FEV(1), and fractional exhaled nitric oxide (FeNO) at the end of treatment period.
Eighty-three patients completed the study. ACQ5 scores improved and exceeded the clinically meaningful difference after 12 weeks of treatment and well-controlled asthma (ACQ5 score ≤0.75) was attained in 37 (44.6%) patients. Minimum and maximum PEF and FEV(1) values improved significantly, but not FeNO values, after switching from SFC to FBC.
Switching ICS/LABA combination therapy is a useful option in the management of asthma that is not optimally controlled.
Allergology International 03/2012; 61(2):323-9.
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Yuzo Suzuki,
Takafumi Suda,
Kazuki Furuhashi,
Kiyoshi Shibata,
Dai Hashimoto,
Noriyuki Enomto,
Tomoyuki Fujisawa,
Yutaro Nakamura, Naoki Inui,
Hirotoshi Nakamura,
Kingo Chida
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ABSTRACT: Lung dendritic cells (LDCs) are primary antigen-presenting cells that develop IgA-producing plasma cells in the lung through class switch recombination (CSR) in naive B cells. Recently, the major LDC subsets were found to comprise CD103(-)CD11b(high) LDCs (CD11b(high) LDCs) and CD103(+)CD11b(low or negative) LDCs (CD103(+) LDCs), but their abilities to induce IgA production have not been defined. Under T cell-dependent (T-D) and T cell-independent (T-ID) conditions, we compared the abilities of these two LDC populations to induce IgA. CD11b(high) or CD103(+) LDCs obtained from BALB/c mice were cocultured with naive IgD(+) B cells in the presence of LPS, with or without anti-CD40 monoclonal antibody (mAb) (i.e., T-D and T-ID coculture conditions, respectively). Under both T-D and T-ID conditions, CD11b(high) LDCs induced significantly greater amounts of IgA production, together with a significantly higher mRNA expression of activation-induced cytidine deaminase, than did CD103(+) LDCs. However, the protein expression of a proliferation-inducing ligand, B cell-activating factor of the tumor necrosis family, or retinaldehyde dehydrogenase-1 did not differ between the two LDC subsets. CD11b(high) LDCs displayed a significantly greater capacity to secrete IL-6 and IL-10 in response to LPS, with or without anti-CD40 mAb. Moreover, the IgA production induced by CD11b(high) LDCs in T-D coculture was attenuated by neutralizing both IL-6 and IL-10. These findings suggest that, of the two major LDCs, CD11b(high) LDCs more efficiently induce IgA than do CD103(+) LDCs, possibly through their potent capacity to produce IgA-inducing cytokines.
American Journal of Respiratory Cell and Molecular Biology 01/2012; 46(6):773-80. · 5.13 Impact Factor
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Yuzo Suzuki,
Takafumi Suda,
Kazuhiro Asada,
Seiichi Miwa,
Masako Suzuki,
Michio Fujie,
Kazuki Furuhashi,
Yutaro Nakamura, Naoki Inui,
Toshihiro Shirai,
Hiroshi Hayakawa,
Hirotoshi Nakamura,
Kingo Chida
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ABSTRACT: Tuberculosis (TB) continues to be a major health problem, and there are few biomarkers for predicting prognosis. Indoleamine 2,3-dioxygenase (IDO), a potent immunoregulatory molecule, catalyzes the rate-limiting step of tryptophan (Trp) degradation in the kynurenine (Kyn) pathway. An increase in IDO activity determined by the serum Trp/Kyn ratio has been shown to be associated with poor prognosis in cancers and bacteremia. In TB, however, there are no studies measuring serum IDO activity to determine its clinical significance. We evaluated serum IDO activity with 174 pulmonary TB (PTB) patients and 85 controls, using liquid chromatography/electrospray ionization tandem mass spectrometry. IDO activity was estimated by calculating the serum Kyn-to-Trp ratio. PTB patients had significantly higher Kyn concentrations and IDO activity and significantly lower Trp concentrations (P < 0.0001, P < 0.0001, and P < 0.0001, respectively) than the controls. Of 174 PTB patients, 39 (22.4%) died. The patients who died had significantly higher concentrations of Kyn and significantly lower Trp concentrations, resulting in significantly higher IDO activity (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). In a receiver operating characteristic (ROC) analysis, serum IDO activity had the highest area under the curve (0.850), and this activity was an independent prognostic factor in multivariate analysis. These results suggest that serum IDO activity can be used as a novel prognostic marker in PTB.
Clinical and vaccine immunology: CVI 01/2012; 19(3):436-42. · 2.37 Impact Factor
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ABSTRACT: We herein report a case of cytomegalovirus (CMV) bronchitis in a 62-year-old woman with polymyositis. She presented with respiratory symptoms and CMV antigenemia while undergoing immunosuppressive therapy with methotrexate (MTX) and prednisolone (PSL). Bronchoscopy was performed, which revealed an ulceration of the left main bronchus. A mucosal biopsy confirmed CMV infection, and the patient was diagnosed with CMV ulcerating bronchitis. The administration of ganciclovir improved the lesion, and the CMV antigenemia disappeared. Endobronchial ulceration should be considered in the differential diagnosis of CMV disease.
Internal Medicine 01/2012; 51(20):2933-6. · 0.94 Impact Factor
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Kazuki Furuhashi,
Takafumi Suda,
Hirotsugu Hasegawa,
Yuzo Suzuki,
Dai Hashimoto,
Noriyuki Enomoto,
Tomoyuki Fujisawa,
Yutaro Nakamura, Naoki Inui,
Kiyoshi Shibata,
Hirotoshi Nakamura,
Kingo Chida
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ABSTRACT: Mouse lung dendritic cells (LDCs) have been recently shown to contain two major subpopulations: CD103(+) CD11b(low or negative) (CD103(+) LDCs) and CD103(-) CD11b(high) LDCs (CD11b(high) LDCs). Although several studies have demonstrated functional differences between them, it is unclear whether the subpopulations induce distinct T helper (Th) cell responses. The present study was conducted to examine whether CD103(+) and CD11b(high) LDCs preferentially generate different Th responses. Naive DO11.10 CD4(+) T cells were primed with CD103(+) or CD11b(high) LDCs obtained from normal BALB/c mice. The primed CD4(+) T cells were restimulated, and their cytokine secretions were assessed. The expression of intracellular cytokines and the mRNA levels of chemokine receptors were also measured. We found that the CD4(+) T cells primed with CD103(+) LDCs secreted significantly larger amounts of IFN-γ and IL-17A, whereas those primed with CD11b(high) LDCs released significantly higher levels of IL-4, IL-6, and IL-10. Intracellular cytokine assay showed that CD103(+) LDCs induced greater frequencies of CD4(+) T cells producing IFN-γ and IL-17A, whereas CD11b(high) LDCs were more efficient at inducing CD4(+) T cells producing IL-4 and IL-10. The mRNA levels of CXCR3 and CCR5, which are expressed preferentially in Th1 cells, were significantly higher in CD4(+) T cells primed with CD103(+) LDCs. The mRNA levels of CXCR4 and CCR4, which are expressed primarily in Th2 cells, were significantly greater in those primed with CD11b(high) LDCs. These data suggest that mouse CD103(+) LDCs predominantly elicit Th1 and Th17 responses, whereas CD11b(high) LDCs primarily provoke a Th2 response under the steady state.
American Journal of Respiratory Cell and Molecular Biology 08/2011; 46(2):165-72. · 5.13 Impact Factor
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ABSTRACT: Multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1) are ATP-binding cassette transporters that mediate the efflux of a broad spectrum of substances and xenobiotics from cells in barrier organs. Interestingly, they are expressed in immune cells including some kinds of dendritic cells (DCs). In the present study, the expressions and activities of MDR1 and MRP1 in mouse lung DCs (LDCs) were investigated.
We purified LDCs comprising ~98% MHC-Class II(+)/CD11c(+) cells using magnetic and flow cytometric cell sorting. The highly purified LDCs expressed MDR1 and MRP1 at both the mRNA and protein levels. The fluorescent probes rhodamine 123 and Fluo-3 were used as substrates in efflux assays to measure the transport activities of MDR1 and MRP1, respectively.
MDR1 blockade by the specific inhibitor verapamil reduced the percentage of rhodamine 123(low) cells in LDCs (from 31.8±6.3% to 11.8±2.8%, p<0.02). MRP1 blockade by the specific inhibitor MK-571 reduced the percentage of Fluo-3(low) cells in LDCs (from 53.8±1.7% to 26.8±6.4%, p<0.03).
These data showed that LDCs exhibited MDR1- and MRP1-mediated efflux activities. MDR1 and MRP1 in LDCs may be involved in protective functions through their efflux activities.
Life sciences 08/2011; 89(7-8):282-7. · 2.56 Impact Factor
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Masato Kono,
Yutaro Nakamura,
Takafumi Suda,
Masato Kato,
Yusuke Kaida,
Dai Hashimoto, Naoki Inui,
Etsuko Hamada,
Osamu Miyazaki,
Syunsuke Kurashita,
Isamu Fukamachi,
Koki Endo,
Poh-Sing Ng,
Kazuhiko Takehara,
Hirotoshi Nakamura,
Masato Maekawa,
Kingo Chida
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ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal pulmonary fibrotic disease and useful biomarkers are required to diagnose and predict disease activity. CCN2 (connective tissue growth factor; CTGF) has been reported as one of the key profibrotic factors associated with transforming growth factor-β (TGF-β), and its assay has potential as a non-invasive measure in various fibrotic diseases. Recently, we developed a new subtraction method for determination of plasma CCN2 levels. We examined the utility of plasma CCN2 levels as a surrogate marker in IPF.
Plasma CCN2 levels were calculated in 33 patients with IPF, 14 patients with non-IPF idiopathic interstitial pneumonias (IIPs) and 101 healthy volunteers by sandwich enzyme-linked immunosorbent assay (ELISA) using specific monoclonal antibodies for two distinct epitopes of human CCN2. We evaluated the utility of plasma CCN2 levels by comparison with clinical parameters.
Plasma CCN2 levels were significantly higher in patients with IPF than in those with non-IPF IIPs and healthy volunteers. Importantly, plasma CCN2 levels showed significantly negative correlation with 6-month change of forced vital capacity (FVC) in patients with IPF.
Plasma CCN2 is a potential biomarker for IPF.
Clinica chimica acta; international journal of clinical chemistry 08/2011; 412(23-24):2211-5. · 2.54 Impact Factor
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Yuzo Suzuki,
Takafumi Suda,
Koushi Yokomura,
Masako Suzuki,
Michio Fujie,
Kazuki Furuhashi,
Dai Hahimoto,
Noriyuki Enomto,
Tomoyuki Fujisawa,
Yutaro Nakamura, Naoki Inui,
Yutaka Nakano,
Hirotoshi Nakamura,
Kingo Chida
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ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step of tryptophan (Trp) degradation in the kynurenine (Kyn) pathway. By depleting Trp, IDO plays a critical role in inducing immune suppression and tolerance. The aim of present study was to investigate serum IDO activity, determined by Kyn-to-Trp ratio (Kyn/Trp ratio), in community-acquired pneumonia (CAP) and to examine its clinical significance. METODS: This study subjects consisted of 129 consecutive patients with CAP and 64 healthy controls. The concentrations of Kyn and Trp were measured simultaneously by liquid chromatography/electrospray ionization tandem mass spectrometry.
The CAP patients had significantly higher Kyn concentrations and significant lower Trp concentrations than the controls (p < 0.0001 and p < 0.0001, respectively). Accordingly, IDO activity was significantly higher (2.4-fold) in the patients than in the controls (p < 0.0001). IDO activity correlated well with PSI (Pneumonia Severity Index) and CURB65 (p = 0.0005 and p < 0.0001, respectively). Moreover, the IDO activity and Kyn concentration were significantly higher in the nonsurvivors and were found to predict mortality in multivariate analysis.
IDO activity was increased in CAP, and this activity was associated with the severity and outcome of this disease. These results suggest that IDO activity can predict prognosis of CAP.
The Journal of infection 07/2011; 63(3):215-22. · 4.13 Impact Factor
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Masato Kato,
Yutaro Nakamura,
Takafumi Suda,
Yuichi Ozawa, Naoki Inui,
Naohiro Seo,
Toshi Nagata,
Yukio Koide,
Pawel Kalinski,
Hirotoshi Nakamura,
Kingo Chida
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ABSTRACT: Staphylococcal enterotoxins A (SEA) and B (SEB) are classical models of superantigens (SAg), which induce potent T-cell-stimulating activity by forming complexes with MHC class II molecules on antigen-presenting cells. This large-scale activation of T-cells is accompanied by increased production of cytokines such as interferon-γ (IFN-γ). Additionally, as we previously reported, IFN-γ-producing CD8(+) T cells act as "helper cells," supporting the ability of dendritic cells to produce interleukin-12 (IL-12)p70. Here, we show that DC pulsed with SAg promote the enhancement of anti-tumor immunity. Murine bone marrow-derived dendritic cells (DC) were pulsed with OVA(257-264) (SIINFEKL), which is an H-2Kb target epitope of EG7 [ovalbumin (OVA)-expressing EL4] cell lines, in the presence of SEA and SEB and were subcutaneously injected into naïve C57BL/6 mice. SAg plus OVA(257-264)-pulsed DC vaccine strongly enhanced peptide-specific CD8(+) T cells exhibiting OVA(257-264)-specific cytotoxic activity and IFN-γ production, leading to the induction of protective immunity against EG7 tumors. Furthermore, cyclophosphamide (CY) added to SAg plus tumor-antigens (OVA(257-264), tumor lysate, or TRP-2) pulsed DC immunization markedly enhanced tumor-specific T-cell expansion and had a significant therapeutic effect against various tumors (EG7, 2LL, and B16). Superantigens are potential candidates for enhancing tumor immunity in DC vaccines.
Cancer Immunology and Immunotherapy 07/2011; 60(7):1029-38. · 3.70 Impact Factor
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Shun Matsuura, Naoki Inui,
Yuichi Ozawa,
Yutaro Nakamura,
Mikio Toyoshima,
Kazumasa Yasuda,
Takashi Yamada,
Toshihiro Shirai,
Hideki Suganuma,
Koji Yokomura,
Takafumi Suda,
Kingo Chida
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ABSTRACT: There are few standard therapeutic options beyond second-line treatment. We aimed to evaluate the efficacy and safety of erlotinib monotherapy as third-line chemotherapy in patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutations.
In this phase II trial, patients who did not have epidermal growth factor receptor mutations and who had previously received two cytotoxic chemotherapy regimens containing platinum were treated with erlotinib (150 mg, per os) until disease progression or unacceptable toxicity.
Twenty patients were eligible for the assessment of efficacy and safety. Three cases showed a partial response, and eight cases showed stable disease with an overall response rate of 15.0% (95% confidence interval: 5.2-36.0%) and a disease control rate of 55.0% (95% confidence interval: 34.2-74.2%). Median progression-free survival and overall survival time were 2.1 and 6.7 months, respectively. Although dose reduction was required in one patient because of skin toxicity, grade 3/4 toxicity or pulmonary disease was not observed.
Erlotinib as third-line therapy showed an acceptable response rate, survival time and toxicity. It could be a potential third-line therapy for patients without epidermal growth factor receptor mutations.
Japanese Journal of Clinical Oncology 06/2011; 41(8):959-63. · 1.78 Impact Factor
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Masato Kono,
Takafumi Suda,
Noriyuki Enomoto,
Yutaro Nakamura,
Yusuke Kaida,
Dai Hashimoto, Naoki Inui,
Tomoaki Mizuguchi,
Akihiko Kato,
Toshihiro Shirai,
Hirotoshi Nakamura,
Kingo Chida
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ABSTRACT: Recently, the potential therapeutic effect of direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been reported for acute exacerbation of interstitial pneumonia (AE-IP), a highly morbid clinical event; however, there is no consensus on the appropriate procedure for PMX-DHP. We examined the appropriate perfusion duration of PMX-DHP for AE-IP.
AE-IP patients receiving PMX-DHP were divided into two groups: short-duration group (≤6 h) (n = 5) and long-duration group (12 h) (n = 12).
ThePaO(2)/FiO(2) (P/F) ratio increased immediately after PMX-DHP in the two groups. In the long-duration group, the P/F ratio continued to increase over the following 7 days, while, in the short-duration group, the P/F ratio declined again 3 days after therapy. The survival rate 30 days after PMX-DHP was significantly higher in the long-duration group than in the short-duration group.
A long perfusion duration of PMX-DHP is more efficacious for AE-IP than a short perfusion duration.
Blood Purification 03/2011; 32(2):75-81. · 2.10 Impact Factor
