Corina N D'Alessandro-Gabazza

Mie University, Tu, Mie, Japan

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Publications (37)187.5 Total impact

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    ABSTRACT: Epithelial to mesenchymal transition (EMT) is a mechanism by which eosinophils can induce airway remodeling. Montelukast, an antagonist of the cysteinyl leukotriene receptor, can suppress airway remodeling in asthma. The purpose of this study was to evaluate whether montelukast can ameliorate airway remodeling by blocking EMT induced by eosinophils. EMT induced was assessed using a co-culture system of human bronchial epithelial cells and human eosinophils or the eosinophilic leukemia cell lines, Eol-1. Montelukast inhibited co-culture associated morphological changes of BEAS-2b cells, decreased the expression of vimentin and collagen I, and increased the expression of E-cadherin. Montelukast mitigated the rise of TGF-β1 production and Smad3 phosphorylation. Co-culture of human eosinophils with BEAS-2B cells significantly enhanced the production of CysLTs compared with BEAS-2B cells or eosinophils alone. The increase of CysLTs was abolished by montelukast pre-treatment. Montelukast had similar effects when co-culture system of Eol-1 and BEAS-2B was used. This study showed that montelukast suppresses eosinophils-induced EMT of airway epithelial cells. This finding may explain the mechanism of montelukast-mediated amelioration of airway remodeling in bronchial asthma.
    Biochemical and Biophysical Research Communications 05/2014; · 2.28 Impact Factor
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    ABSTRACT: Background: Thrombomodulin treatment modulates the properties of dendritic cells (DCs) converting them from immunogenic to tolerogenic and inducing its own expression on DCs. Thrombomodulin binds to the inflammatory mediator, high mobility group protein B1 (HMGB1), antagonizing signalling through its receptor, receptor for advanced glycation end products (RAGE). Methods: To test if soluble thrombomodulin could antagonize HMGB1 signaling via RAGE on DCs. DCs were prepared from mouse bone marrow cells or human monocytes. In some experiments dendritic cells were sorted into thrombomodulin+ and thrombomodulin- populations. Expression of surface maturation markers was determined by flow cytometry following treatment with thrombomodulin in the presence or absence of HMGB1. Results: Thrombomodulin+ dendritic cells secrete less HMGB1 into the medium. HMGB1 reduces the effects of thrombomodulin on expression of DC maturation markers. Treatment with thrombomodulin reduces the expression of maturation markers such as CD80 and CD86 and increases the expression of thrombomodulin on the DC surface. Treatment of DCs with neutralizing anti-HMGB1 antibody acted synergistically with thrombomodulin in increasing thrombomodulin expression on DCs. Treatment with thrombomodulin can still reduce the expression of surface markers on DCs derived from mice that are deficient in RAGE showing that thrombomodulin can affect DCs by an alternative mechanism. Conclusions: The results of this study show that thrombomodulin modulates DCs both by antagonizing the interaction of HMGB1 with RAGE and by an independent mechanism.
    Allergology International 12/2013;
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    ABSTRACT: Apart from its role in the coagulation system, thrombin plays an important role in the inflammatory response through its protease-activated receptor(PAR)s. However, the role of thrombin in the immune response is not clear. We evaluated if thrombin has a modulatory role in allergic bronchial asthma. Bronchial asthma was induced in mice by intraperitoneal sensitization and inhalation challenge with ovalbumin. Thrombin or its inhibitors were administered by inhalation before each allergen challenge. Mice with low but sustained coagulation activation had reduced allergic inflammation and allergic asthma was inhibited by low doses but worsened by high doses of thrombin. Allergic asthma was worsened by antithrombin, argatroban, hirudin and anti-thrombomodulin antibody. Mice with an increased concentration of an inhibitor of both thrombin and activated protein C had worsened disease. Heterozygous PAR-1 mice had less allergic inflammation but PAR-1 agonist worsened it. Allergic bronchial inflammation was worsened in mice that received adoptive transfer of PAR-1 agonist-treated Th2 cells compared to controls. Low concentrations of thrombin suppressed but high-dose of it enhanced maturation and secretion of cytokines in dendritic cells. The effects of thrombin on allergic asthma are dose-dependent with detrimental effects at high dose and protective ones at low dose. These data demonstrate that thrombin modulates the outcome in allergic bronchial asthma. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 08/2013; · 6.08 Impact Factor
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    ABSTRACT: Background: Acute lung injury (ALI) is a devastating disease with an overall mortality rate of 30~40%. The coagulation/fibrinolysis system is implicated in the pathogenesis of ALI. Thrombin-activatable fibronolysis inhibitor (TAFI) is an important component of the fibrinolysis system. Recent studies have shown that TAFIa can also regulate inflammatory responses by its ability to inhibit complement C3a and C5a, and osteopontin. Objective: We hypothesized that TAFI might have a protective role in ALI. To demonstrate this hypothesis the development of ALI was compared between wild type and TAFI-deficient mice. Methods: ALI was induced by intratracheal instillation of lipopolysaccharide (LPS). Control mice were treated with saline. Animals were sacrificed 24 hours after LPS. Results: The number of inflammatory cells and the concentration of total protein and inflammatory cytokines were significantly increased in BALF from LPS-treated TAFI-deficient mice compared to their wild type counterparts. Significantly higher concentrations of C5a were found in BALF and plasma in LPS-treated TAFI KO mice compared to wild type mice. Pre-treatment with inhaled C5a receptor antagonist blocked the detrimental effects of TAFI deficiency to levels of wild type mice. Conclusions: TAFI protects against acute lung injury, at least in part, by inhibiting the complement system.
    American Journal of Respiratory Cell and Molecular Biology 05/2013; · 4.15 Impact Factor
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    ABSTRACT: Eosinophilic inflammation and remodeling of the airways including subepithelial fibrosis and myofibroblast hyperplasia are characteristic pathological findings of bronchial asthma. Epithelial to mesenchymal transition (EMT) plays a critical role in airway remodelling. In this study, we hypothesized that infiltrating eosinophils promote airway remodelling in bronchial asthma. To demonstrate this hypothesis we evaluated the effect of eosinophils on EMT by in vitro and in vivo studies. EMT was assessed in mice that received intra-tracheal instillation of mouse bone marrow derived eosinophils and in human bronchial epithelial cells co-cultured with eosinophils freshly purified from healthy individuals or with eosinophilic leukemia cell lines. Intra-tracheal instillation of eosinophils was associated with enhanced bronchial inflammation and fibrosis and increased lung concentration of growth factors. Mice instilled with eosinophils pre-treated with transforming growth factor(TGF)-β1 siRNA had decreased bronchial wall fibrosis compared to controls. EMT was induced in bronchial epithelial cells co-cultured with human eosinophils and it was associated with increased expression of TGF-β1 and Smad3 phosphorylation in the bronchial epithelial cells. Treatment with anti-TGF-β1 antibody blocked EMT in bronchial epithelial cells. Eosinophils induced EMT in bronchial epithelial cells, suggesting their contribution to the pathogenesis of airway remodelling.
    PLoS ONE 01/2013; 8(5):e64281. · 3.53 Impact Factor
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    ABSTRACT: Previously we have shown in a mouse model of bronchial asthma that thrombomodulin can convert immunogenic conventional dendritic cells into tolerogenic dendritic cells while inducing its own expression on their cell surface. Thrombomodulin(+) dendritic cells are tolerogenic while thrombomodulin(-) dendritic cells are pro-inflammatory and immunogenic. Here we hypothesized that thrombomodulin treatment of dendritic cells would modulate inflammatory gene expression. Murine bone marrow-derived dendritic cells were treated with soluble thrombomodulin and expression of surface markers was determined. Treatment with thrombomodulin reduces the expression of maturation markers and increases the expression of TM on the DC surface. Thrombomodulin treated and control dendritic cells were sorted into thrombomodulin(+) and thrombomodulin(-) dendritic cells before their mRNA was analyzed by microarray. mRNAs encoding pro-inflammatory genes and dendritic cells maturation markers were reduced while expression of cell cycle genes were increased in thrombomodulin-treated and thrombomodulin(+) dendritic cells compared to control dendritic cells and thrombomodulin(-) dendritic cells. Thrombomodulin-treated and thrombomodulin(+) dendritic cells had higher expression of 15-lipoxygenase suggesting increased synthesis of lipoxins. Thrombomodulin(+) dendritic cells produced more lipoxins than thrombomodulin(-) dendritic cells, as measured by ELISA, confirming that this pathway was upregulated. There was more phosphorylation of several cell cycle kinases in thrombomodulin(+) dendritic cells while phosphorylation of kinases involved with pro-inflammatory cytokine signaling was reduced. Cultures of thrombomodulin(+) dendritic cells contained more cells actively dividing than those of thrombomodulin(-) dendritic cells. Production of IL-10 is increased in thrombomodulin(+) dendritic cells. Antagonism of IL-10 with a neutralizing antibody inhibited the effects of thrombomodulin treatment of dendritic cells suggesting a mechanistic role for IL-10. The surface of thrombomodulin(+) dendritic cells supported activation of protein C and procarboxypeptidase B2 in a thrombomodulin-dependent manner. Thus thrombomodulin treatment increases the number of thrombomodulin(+) dendritic cells, which have significantly altered gene expression compared to thrombomodulin(-) dendritic cells in key immune function pathways.
    PLoS ONE 01/2013; 8(8):e72392. · 3.53 Impact Factor
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    ABSTRACT: Regulatory T cells (Tregs) are a specific subset of T lymphocytes that regulate the function of other subsets of lymphocytes. Contradictory results have been reported regarding the role of Tregs in lung fibrosis. We wished to clarify the role of Tregs in the early and late stages of bleomycin-induced lung fibrosis in mice by depleting them with anti-CD25+ antibody (PC61). Mice treated with PC61 in early stages had significantly decreased number of CD4+CD25+ T cells compared to mice treated with the isotype control. The number of inflammatory cells, the concentrations of collagen, TGFβ1, the content of collagen and hydroxyproline in lung tissue were significantly reduced in PC61-treated mice compared to mice treated with the isotype control group. Pathological examination of the lung also disclosed reduced fibrotic changes and decreased fibrosis score in the PC61 group compared to control group. By contrast, mice treated with PC61 in late stages of the disease showed more infiltration of inflammatory cells and higher fibrotic score and hydroxyproline content in the lungs than mice treated with the isotype control. Our results suggest that Tregs play a detrimental role in early stages but protective role in late stages of pulmonary fibrosis in mice.
    Immunobiology 05/2012; · 2.81 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of transforming growth factor (TGF)-β1 as the major player in the pathogenesis of the disease. However, attempts to control its expression and to improve the outcome of pulmonary fibrosis have been disappointing. We tested the hypothesis that TGF-β1 is the dominant factor in the acute and chronic phases of pulmonary fibrosis and developed short interfering (si)RNAs directed toward molecules implicated in the disease. This study developed novel sequences of siRNAs targeting the TGF-β1 gene and evaluated their therapeutic efficacy in two models of pulmonary fibrosis: a model induced by bleomycin and a novel model of the disease developed spontaneously in mice overexpressing the full length of human TGF-β1 in the lungs. Intrapulmonary delivery of aerosolized siRNAs of TGF-β1 with sequences common to humans and rodents significantly inhibited bleomycin-induced pulmonary fibrosis in the acute and chronic phases of the disease and in a dose-dependent manner. Aerosolized human-specific siRNA also efficiently inhibited pulmonary fibrosis, improved lung function, and prolonged survival in human TGF-β1 transgenic mice. Mice showed no off-target effects after intratracheal administration of siRNA. These results suggest the applicability of these novel siRNAs as tools for treating pulmonary fibrosis in humans.
    American Journal of Respiratory Cell and Molecular Biology 03/2012; 46(3):397-406. · 4.15 Impact Factor
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    ABSTRACT: Activated protein C (APC) can regulate immune and inflammatory responses and apoptosis. Protein C transgenic mice develop less diabetic nephropathy but whether exogenous administration of APC suppresses established diabetic nephropathy is unknown. We investigated the therapeutic potential of APC in mice with streptozotocin-induced diabetic nephropathy. Diabetes was induced in unilaterally nephrectomized C57/Bl6 mice using intraperitoneal (i.p.) injection of streptozotocin. Four weeks later, the mice were treated with i.p. exogenous APC every other day for 1 month. APC-treated mice had a significantly improved blood nitrogen urea-to-creatinine ratio, urine total protein to creatinine ratio and proteinuria, and had significantly less renal fibrosis as measured by the levels of collagen and hydroxyproline. The renal tissue concentration of monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and the RNA expression of platelet-derived growth factor (PDGF), transforming growth factor-β1 and connective tissue growth factor (CTGF) were significantly lower in APC-treated mice than in untreated animals. The percentage of apoptotic cells was reduced and the expression of podocin, nephrin and WT-1 in the glomeruli was significantly improved in mice treated with APC compared with untreated mice. The levels of coagulation markers were not affected by APC treatment. Exogenous APC improves renal function and mitigates pathological changes in mice with diabetic nephropathy by suppressing the expression of fibrogenic cytokines, growth factors and apoptosis, suggesting its potential usefulness for the therapy of this disease.
    Journal of Thrombosis and Haemostasis 03/2012; 10(3):337-46. · 6.08 Impact Factor
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    ABSTRACT: RNA interference (RNAi) is being widely used in functional gene research and is an important tool for drug discovery. However, canonical double-stranded short interfering RNAs are unstable and induce undesirable adverse effects, and thus there is no currently RNAi-based therapy in the clinic. We have developed a novel class of RNAi agents, and evaluated their effectiveness in vitro and in mouse models of acute lung injury (ALI) and pulmonary fibrosis. The novel class of RNAi agents (nkRNA®, PnkRNA™) were synthesized on solid phase as single-stranded RNAs that, following synthesis, self-anneal into a unique helical structure containing a central stem and two loops. They are resistant to degradation and suppress their target genes. nkRNA and PnkRNA directed against TGF-β1mRNA ameliorate outcomes and induce no off-target effects in three animal models of lung disease. The results of this study support the pathological relevance of TGF-β1 in lung diseases, and suggest the potential usefulness of these novel RNAi agents for therapeutic application.
    PLoS ONE 01/2012; 7(8):e42655. · 3.53 Impact Factor
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    ABSTRACT: Bronchial asthma is an inflammatory disease of the airways. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase that besides inhibiting fibrinolysis, also regulates inflammatory processes. The only validated substrate known for TAFI is fibrin. In the present study we evaluated the role of TAFI in bronchial asthma by comparing the development of allergic bronchial asthma between wild-type (WT) and TAFI-deficient mice (KO). Asthmatic inflammation was induced by sensitization and challenge with ovalbumin in WT (WT/OVA) and TAFI KO (KO/OVA) mice. WT mice (WT/SAL) and TAFI KO (KO/SAL) were used as controls. Cytokines, markers of inflammation, and coagulation were measured in bronchoalveolar lavage fluid (BALF). Airway hyperresponsiveness was worse in KO/OVA mice than in WT/OVA mice or control mice. Markers of lung injury were significantly increased in BALF from KO/OVA mice compared to WT/OVA mice. Airway hyperresponsiveness and the BALF concentrations of IL-5 and osteopontin were significantly increased in KO/OVA mice compared to WT/OVA mice. Treatment of WT/OVA and KO/OVA mice with a C5a receptor antagonist significantly decreased hyperresponsiveness along with the BALF concentrations of total protein and C5a compared to untreated asthmatic mice. The results of this study suggest that TAFI plays a protective role in the pathogenesis of allergic inflammation probably by inhibiting the complement system.
    Beiträge zur Klinik der Tuberkulose 10/2011; 190(2):189-98. · 2.06 Impact Factor
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    ABSTRACT: A moderate intake of alcohol is associated with lower cardiovascular mortality, and the role of circulating progenitor cells in the beneficial effect of alcohol on atherosclerosis is unclear. The hypothesis of this study was that alcohol ameliorates atherosclerosis by modulating the circulating levels of stromal cell-derived growth factor (SDF)-1 and vascular progenitor cells. Atherosclerosis was induced by infusion of angiotensin II in apolipoprotein-E deficient mice, which were treated with high and low doses of ethanol for 28 days by intraperitoneal injection. Mice treated with low-dose ethanol had significantly less dilatation and fewer atheromatous lesions than mice receiving the high-dose ethanol. The number of circulating fibrocytes was significantly lower in mice treated with high-dose ethanol compared with mice with atherosclerosis untreated with ethanol. The plasma CXCL12/SDF-1 level was significantly increased in mice treated with low-dose ethanol compared with mice treated with a high dose, and the plasma concentration of transforming growth factor-β1 was significantly increased in mice treated with high-dose ethanol compared with control mice. Ethanol regulated the secretion of SDF-1 and vascular endothelial growth factor from fibroblasts in a dose-dependent and bimodal fashion. The circulating level of CXCL12/SDF-1 may be involved, at least in part, in the differential effects of alcohol consumption on atherosclerosis.
    Circulation Journal 07/2011; 75(9):2269-79. · 3.58 Impact Factor
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    Journal of Allergy and Clinical Immunology - J ALLERG CLIN IMMUNOL. 01/2011; 127(2).
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    ABSTRACT: bronchial asthma is caused by inappropriate acquired immune responses to environmental allergens. It is a major health problem, with a prevalence that is rapidly increasing. Curative therapy is not currently available. to test the hypothesis that thrombomodulin (TM) inhibits allergic bronchial asthma by inducing tolerogenic dendritic cells (DCs). the protective effect of TM was evaluated using a murine asthma model. Asthma was induced in mice by exposure to chicken egg ovalbumin, and the effects of inhaled TM or TM-treated DCs were assessed by administering before ovalbumin exposure. treatment with TM protects against bronchial asthma measured as improved lung function and reduced IgE and cells in alveolar lavage fluid by inducing tolerogenic dendritic dells. These are characterized by high expression of surface TM (CD141/TM(+)) and low expression of maturation markers and possess reduced T-cell costimulatory activity. The CD141/TM(+) DCs migrate less toward chemokines, and after TM treatment there are fewer DCs in the draining lymph node and more in the lungs. The TM effect is independent of its role in coagulation. Rather, it is mediated via the TM lectin domain directly interacting with the DCs. the results of this study show that TM is a modulator of DC immunostimulatory properties and a novel candidate drug for the prevention of bronchial asthma in atopic patients.
    American Journal of Respiratory and Critical Care Medicine 01/2011; 183(1):31-42. · 11.04 Impact Factor
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    ABSTRACT: Activation of the complement system has been implicated in tumor growth. The antifibrinolytic protein, activated thrombin-activatable fibrinolysis inhibitor (TAFIa), can modulate the activation of the complement system by inactivating the anaphylatoxins C3a and C5a. The apolipoprotein-E (ApoE) genotype has been associated with carcinogenesis. The aim of this study was to evaluate whether TAFIa can affect the development of cancer in the ApoE-deficient mouse model. Methods: TAFI and ApoE double-knockout mice were generated. A group of mice was treated with the diabetogenic and carcinogenic compound streptozotocin (stz). Mice treated with saline, single knockout mice and wild-type (wt) mice served as controls. Six months after treatment with stz, mice were sacrificed. Hepatic tumors were found in male double-knockout mice treated with stz but none was found in control animals that were not treated with stz or in single knockout of ApoE or wt animals. There was no significant difference in coagulation system activation between the groups of mice. The plasma concentrations of C5a, factor D and transforming growth factor-β1 were increased in TAFI/ApoE double-deficient mice treated with stz compared with the mice of the same genotype treated with saline. Apo-E deficiency alone was not associated with tumors but the lack of TAFI appears to make the mice permissive for tumor formation in ApoE mice.
    Journal of Thrombosis and Haemostasis 11/2010; 8(11):2514-22. · 6.08 Impact Factor
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    ABSTRACT: The rapid increase in the elderly population is leading to a corresponding increase in the number of people requiring medical care. To date no comparative study between community-acquired pneumonia (CAP) and nursing home-acquired pneumonia (NHAP) has been reported in the very elderly non-intubated patients. The present study was undertaken to compare the clinical characteristics and microbial etiology between CAP and NHAP in elderly patients >/=85-years old. There were 54 patients with NHAP and 47 with CAP. Performance status was significantly worse in the NHAP than in the CAP group. Among all patients, the most frequent pathogens were Chlamydophilia pneumoniae followed by Streptococcus pneumoniae, Mycoplasma pneumoniae influenza virus and Staphylococcus aureus. The frequency of S. peumoniae was significantly higher in NHAP patients than in CAP patients after adjusting for age and sex. Physical activity, nutrition status and dehydration were significant prognostic factors of pneumonia among all patients. In-hospital mortality was significantly higher in NHAP than in CAP after adjusting for age and sex. This study demonstrated that the etiology and clinical outcome differ between CAP and NHAP patients in the very elderly non-intubated population.
    Respiratory medicine 04/2010; 104(4):584-92. · 2.33 Impact Factor
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    ABSTRACT: The fibrinolytic system has been implicated in the pathogenesis of pulmonary hypertension (PH). Thrombin-activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis and therefore its absence would be expected to increase fibrinolysis and ameliorate PH. The objective of the present study was to evaluate the effect of TAFI deficiency on pulmonary hypertension in the mouse. PH was induced in C57/Bl6 wild-type (WT) or TAFI-deficient (KO) mice by weekly subcutaneous treatment with 600 mg kg(-1) monocrotaline (MCT) for 8 weeks. PH was inferred from right heart hypertrophy measured using the ratio of right ventricle-to-left ventricle-plus-septum weight [RV/(LV+S)]. Pulmonary vascular remodeling was analyzed by morphometry. TAFI-deficient MCT-treated and wild-type MCT-treated mice suffered similar weight loss. TAFI-deficient MCT-treated mice had reduced levels of total protein and tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor-beta (TGF-beta) and monocyte chemoattractant protein-1 (MCP-1) in bronchial alveolar lavage compared with wild-type MCT-treated mice. The ratio of RV to (LV+S) weight was significantly higher in WT/MCT than in KO/MCT mice. The pulmonary artery wall area and vascular stenosis were both greater in MCT-treated WT mice compared with MCT-treated TAFI-deficient mice. TAFI-deficient MCT-treated mice had less pulmonary hypertension, vascular remodeling and reduced levels of cytokines compared with MCT-treated WT animals, possibly as a result of reduced coagulation activation.
    Journal of Thrombosis and Haemostasis 04/2010; 8(4):808-16. · 6.08 Impact Factor
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    ABSTRACT: To determine the efficacy of a 23-valent pneumococcal polysaccharide vaccine in people at high risk of pneumococcal pneumonia. Prospective, randomised, placebo controlled double blind study. Nursing homes in Japan. 1006 nursing home residents. Participants were randomly allocated to either 23-valent pneumococcal polysaccharide vaccine (n=502) or placebo (n=504). The primary end points were the incidence of all cause pneumonia and pneumococcal pneumonia. Secondary end points were deaths from pneumococcal pneumonia, all cause pneumonia, and other causes. Pneumonia occurred in 63 (12.5%) participants in the vaccine group and 104 (20.6%) in the placebo group. Pneumococcal pneumonia was diagnosed in 14 (2.8%) participants in the vaccine group and 37 (7.3%) in the placebo group (P<0.001). All cause pneumonia and pneumococcal pneumonia were significantly more frequent in the placebo group than in the vaccine group: incidence per 1000 person years 55 v 91 (P<0.0006) and 12 v 32 (P<0.001), respectively. Death from pneumococcal pneumonia was significantly higher in the placebo group than in the vaccine group (35.1% (13/37) v 0% (0/14), P<0.01). The death rate from all cause pneumonia (vaccine group 20.6% (13/63) v placebo group 25.0% (26/104), P=0.5) and from other causes (vaccine group 17.7% (89/502) v placebo group (80/504) 15.9%, P=0.4) did not differ between the two study groups. The 23-valent pneumococcal polysaccharide vaccine prevented pneumococcal pneumonia and reduced mortality from pneumococcal pneumonia in nursing home residents. Trial registration Japan Medical Association Center for Clinical Trials JMA-IIA00024.
    BMJ (online) 01/2010; 340:c1004. · 17.22 Impact Factor
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    ABSTRACT: Protein S may exert an anticoagulant activity by enhancing the anticoagulant activity of activated protein C and/or by directly inhibiting the prothrombinase complex. Protein S itself may also directly regulate inflammatory responses and apoptosis. The role of protein S in acute lung injury (ALI) was unknown. This study evaluated the effect of protein S on ALI in the mouse. Animal ALI was induced in C57/BL6 mice by intratracheal instillation of lipopolysaccharide (LPS). Mice were treated with protein S or saline by intraperitoneal injection 1 h before LPS instillation. Activated protein or protein S alone and combined activated protein C + protein S therapy decreased inflammatory markers and cytokines in mice with acute lung injury. In LPS-treated mice compared with controls ALI was induced as shown by significantly increased levels of total protein, tumor necrosis factor-alpha, interleukin-6 and monocyte chemoattractant protein-1 in the bronchoalveolar lavage fluid. Mice with ALI treated with protein S had significantly decreased concentrations of tumor necrosis factor-alpha and interleukin-6 in the lung compared with untreated animals. Thrombin-antithrombin III, a marker of the activity of the coagulation cascade, was unchanged. Protein S inhibited the expression of cytokines in vitro and increased activation of the Axl tyrosine kinase pathway in A549 epithelial cells. Protein S protects against LPS-induced ALI, possibly by directly inhibiting the local expression of inflammatory cytokines without affecting coagulation.
    Journal of Thrombosis and Haemostasis 10/2009; 7(12):2053-63. · 6.08 Impact Factor
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    ABSTRACT: Patients with obstructive sleep apnea (OSA) have a high frequency of cardiovascular diseases and hypercoagulability is believed to be involved in the mechanism of those vascular events. We evaluated whether there is a dysfunction in the protein C anticoagulant pathway in patients with obstructive sleep apnea. Two hundred ninety-three patients were enrolled. To confirm the diagnosis of OSA, all-night polysomnography, including determination of SpO(2), was carried out. The apnea-hypopnea index (AHI) was used for judging the presence of sleep-breathing disorder. The plasma levels of the thrombin-antithrombin complex were higher in patients with AHI > 5 than in those without OSA, defined as AHI < 5. However, there was no statistically significant difference in the plasma level of either activated protein C/alpha-antitrypsin complex or soluble thrombomodulin between patients with AHI > 5 and those with AHI < 5. The results of this study showed for the first time that markers of the protein C anticoagulant pathway are not affected in patients with OSA and that the protein C pathway is probably not involved in the mechanism of hypercoagulability in subjects with sleep-disordered breathing.
    Beiträge zur Klinik der Tuberkulose 06/2009; 187(4):209-13. · 2.06 Impact Factor