Biomedical subjects

Koichi Hashimoto

Publications and source records attributed to Koichi Hashimoto.

18 recordsLinked to original sources

PubMed2007

Prostaglandin I2 analogs inhibit proinflammatory cytokine production and T cell stimulatory function of dendritic cells.

Signaling through the PGI(2) receptor (IP) has been shown to inhibit inflammatory responses in mouse models of respiratory syncytial viral infection and OVA-induced allergic responses. However, little is known about the cell types that mediate the anti-inflammatory function of PGI(2.) In this study, we determined that PGI(2) analogs modulate dendritic cell (DC) cytokine production, maturation, and function. We report that PGI(2) analogs (iloprost, cicaprost, treprostinil) differentially modulate the response of murine bone marrow-derived DC (BMDC) to LPS in an IP-dependent manner. The PGI(2) analogs decreased BMDC production of proinflammatory cytokines (IL-12, TNF-alpha, IL-1alpha, IL-6) and chemokines (MIP-1alpha, MCP-1) and increased the production of the anti-inflammatory cytokine IL-10 by BMDCs. The modulatory effect was associated with IP-dependent up-regulation of intracellular cAMP and down-regulation of NF-kappaB activity. Iloprost and cicaprost also suppressed LPS-induced expression of CD86, CD40, and MHC class II molecules by BMDCs and inhibited the ability of BMDCs to stimulate Ag-specific CD4 T cell proliferation and production of IL-5 and IL-13. These findings suggest that PGI(2) signaling through the IP may exert anti-inflammatory effects by acting on DC.

Animals↗

PubMed2006

IL-13 is associated with reduced illness and replication in primary respiratory syncytial virus infection in the mouse.

The role of IL-13 in respiratory syncytial virus (RSV) immunopathogenesis is incompletely described. To assess the effect of IL-13 on primary RSV infection, transgenic mice which either overexpress IL-13 in the lung (IL-13 OE) or non-transgenic littermates (IL-13 NT) were challenged intranasally with RSV. IL-13 OE mice had significantly decreased peak viral titers four days after infection compared to non-transgenic littermates. In addition, IL-13 OE mice had significantly lower RSV-induced weight loss and reduced lung IFN-gamma protein expression compared with IL-13 NT mice. In contrast, primary RSV challenge of IL-13 deficient mice resulted in a small, but statistically significant increase in viral titers on day four after infection, no difference in RSV-induced weight loss compared to wild type mice, and augmented IFN-gamma production on day 6 after infection. In STAT1-deficient (STAT1 KO) mice, where primary RSV challenge produced high levels of IL-13 production in the lungs, treatment with an IL-13 neutralizing protein resulted in greater peak viral titers both four and six days after RSV and greater RSV-induced weight loss compared to mice treated with a control protein. These results suggest that IL-13 modulates illness from RSV-infection.

Animals↗

PubMed2006

A physical model for galvanotaxis of Paramecium cell.

We propose a qualitative physical model of galvanotaxis of Paramecium cells using a bottom-up approach to link the microscopic ciliary motion and the macroscopic behavior of the cells. From the characteristic pattern of ciliary motion called the Ludloff phenomenon, the torque that orients the cell toward the cathode is derived mathematically. Dynamical equations of motion are derived and their stability is discussed. In numerical simulations using our model, cells exhibit realistic behavior, such as U-turns, like real cells.

Animals↗

PubMed2005

Allergen-induced airway hyperresponsiveness mediated by cyclooxygenase inhibition is not dependent on 5-lipoxygenase or IL-5, but is IL-13 dependent.

Cyclooxygenase (COX) inhibition during allergic sensitization and allergen airway challenge results in augmented allergic inflammation. We hypothesized that this increase in allergic inflammation was dependent on increased generation of leukotrienes that results from COX inhibition, as leukotrienes are important proinflammatory mediators of allergic disease. To test this hypothesis, we allergically sensitized and challenged mice deficient in 5-lipoxygenase (5-LO). We found that 5-LO knockout mice that were treated with a COX inhibitor during allergic sensitization and challenge had significantly increased airway hyperresponsiveness (AHR) (p < 0.01) and airway eosinophilia (p < 0.01) compared with 5-LO knockout mice that were treated with vehicle. The proinflammatory cytokines have also been hypothesized to be critical regulators of airway inflammation and AHR. We found that the increase in airway eosinophilia seen with COX inhibition is dependent on IL-5, whereas the increase in AHR is not dependent on this cytokine. In contrast, the COX inhibition-mediated increase in AHR is dependent on IL-13, but airway eosinophilia is not. These results elucidate the pathways by which COX inhibition exerts a critical effect of the pulmonary allergen-induced inflammatory response and confirm that COX products are important regulators of allergic inflammation.

Allergens↗

PubMed2005

Cyclooxygenase inhibition augments allergic inflammation through CD4-dependent, STAT6-independent mechanisms.

Nonselective cyclooxygenase (COX) inhibition during the development of allergic disease in a murine model causes an increase in type 2 cytokines and lung eosinophilia; however, the mechanisms responsible for this augmented allergen-induced inflammation have not been examined. Ab depletion of CD4 and CD8 cells revealed that the heightened allergic inflammation caused by COX inhibition was CD4, but not CD8, dependent. Allergen sensitization and airway challenge alone led to undetectable levels of IL-5 and IL-13 in the lungs of IL-4, IL-4Ralpha, and STAT6 knockout (KO) mice, but COX inhibition during the development of allergic inflammation resulted in wild-type levels of IL-5 and IL-13 and heightened airway eosinophilia in each of the three KO mice. These results indicate that the effect of COX inhibition was independent of signaling through IL-4, IL-4Ralpha, and STAT6. However, whereas COX inhibition increased IgE levels in allergic wild-type mice, IgE levels were undetectable in IL-4, IL-4Ralpha, and STAT6 KO mice, suggesting that IL-13 alone is not a switch factor for IgE synthesis in this model. These results illustrate the central role played by products derived from the COX pathway in the regulation of allergic immune responses.

Animals↗

PubMed2005

Respiratory syncytial virus infection in the absence of STAT 1 results in airway dysfunction, airway mucus, and augmented IL-17 levels.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading infectious cause of respiratory failure and wheezing in infants and young children. Prematurity is the greatest risk factor for severe RSV-induced disease, and recent studies suggest that premature children have lower levels of the type I IFNs (alpha/beta), for which signal transducer and activator of transcription (STAT) 1 is a critical intracellular signaling molecule. OBJECTIVE: We hypothesized that RSV infection in STAT 1 knockout (STAT 1 KO) mice would result in both increased airway resistance and airway hyperresponsiveness. METHODS: Wild-type (WT) and STAT 1 KO mice on a BALB/c background were either RSV or mock infected. Phenotypic response to infection was assessed by means of plethysmography, immunohistochemistry, and lung cytokine measurement. RESULTS: We found that STAT 1 KO mice infected with RSV (STAT 1 KO-RSV) had greater baseline lung resistance (P=.05) and airway responsiveness (P<.001) than mock-infected STAT 1 KO (STAT 1 KO-MOCK), RSV-infected wild type (WT-RSV), and mock-infected wild type (WT-MOCK) mice. In addition, the STAT 1 KO-RSV mice showed induction of mucus production and expression of gob-5 and Muc5ac, conditions not present in any of the other 3 groups. IL-17, a cytokine that regulates Muc5ac expression, was expressed in the lungs of the STAT 1 KO-RSV mice, whereas lung levels of IL-17 were undetectable in the remaining groups. Expression of the IL-23-specific p19 subunit was also increased in the STAT 1 KO-RSV mice but not in the WT-RSV mice. CONCLUSION: These results show that STAT 1 has an important regulatory role in RSV-induced alteration of airway function.

Animals↗

PubMed2005

Glucose intolerance is common in Japanese patients with acute coronary syndrome who were not previously diagnosed with diabetes.

OBJECTIVE: Postprandial hyperglycemia has emerged as a new glycometabolic condition associated with an excessive risk for coronary artery disease. We therefore attempted to evaluate the frequency of postchallenge hyperglycemia in patients with acute coronary syndrome (ACS) who were not previously diagnosed to have diabetes and did not have a fasting glucose concentration of > or =7 mmol/l or an HbA(1c) level >6.0%. We further correlated the presence of postchallenge hyperglycemia with the extent of coronary atherosclerosis. RESEARCH DESIGN AND METHODS: In all, 134 consecutive ACS patients who met the above inclusion criteria were studied. An oral glucose tolerance test was performed before discharge. RESULTS: The mean age, fasting glucose, and HbA(1c) were 60 years, 5.15 mmol/l, and 5.4%, respectively. Among ACS patients, impaired glucose tolerance (IGT) and diabetes were found in 50 (37%) and 13 patients (10%), respectively. The homeostasis model assessment for insulin resistance did not differ substantially among the normal glucose tolerance (NGT), IGT, and diabetic groups. Insulinogenic index, however, was lower and the number of stenosed vessels higher in diabetic patients compared with NGT patients. CONCLUSIONS: Postchallenge hyperglycemia, caused primarily by impaired initial insulin secretion, is commonly found in Japanese ACS patients who have not been previously diagnosed with diabetes, and this phenomenon is considered to be associated with advanced coronary atherosclerosis. Therefore, the present study strongly supports the notion that oral glucose tolerance test assessment of postchallenge hyperglycemia is essential to identify any previously undiagnosed diabetes cases among Japanese ACS patients.

Acute Disease↗

PubMed2004

Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and gob-5.

Respiratory syncytial virus (RSV) is associated with wheezing and childhood asthma. We previously reported that RSV infection prolongs methacholine-induced airway hyperresponsiveness in ovalbumin (OVA)-sensitized mice. In addition, allergically sensitized RSV-infected (OVA/RSV) mice had more abundant airway epithelial mucus production compared with OVA mice 14 days after infection, whereas there was almost no mucus in mice that were only RSV infected. We hypothesized that this increased mucus was associated with mucosal expression of Muc5ac, a mucus gene expression in airways, and gob-5, a member of the Ca(2)(+)-activated chloride channel family. By histochemical analysis, we found that there was significantly increased staining for gob-5 and Muc5ac in the airways of OVA/RSV mice compared with either OVA mice or allergically sensitized mice that were challenged with inactivated RSV, and virtually no detectable staining in the RSV group. These findings were confirmed by Western blot analysis. The increased mucus expression in the OVA/RSV group was associated with increased lung levels of interleukin-17, a factor known to stimulate airway mucin gene expression. The impact of virus infection combined with allergic inflammation on mucus production may partially explain the more severe disease and airway hyperresponsiveness associated with RSV in the setting of atopy.

Animals↗

PubMed2004

Isolation and characterization of NMSO3-resistant mutants of respiratory syncytial virus.

We obtained two mutant strains of respiratory syncytial virus (RSV) which showed resistance against NMSO3 after 15 and 33 passages, respectively, in HEp-2 cells in the presence of 6.8 microM of NMSO3. The EC50 values of NMSO3 for the resistant virus strains were 0.48 and 0.93 microM, that is 4.8-9.3 times higher than that of the parent strain (EC50 = 0.1 microM). The most resistant strain also showed resistance against heparin but was sensitive to dextran sulfate and a polyoxotungstate, PM-523. In order to determine whether the acquisition of resistance to NMSO3 was the result of the accumulation of genetic changes of virus, we sequenced the G- and F-protein genes. In comparison with the standard type of RSV strains, we identified changes of 10 amino acids in the G protein including those at the central conserved segment. However, we did not observe any particular changes in the amino acid sequence of the F-protein of the resistant strains. From these results, we conclude that NMSO3 inhibits the G-protein interaction to the receptor. The mutations in the G-protein may result in the observed phenotypic resistance of RSV towards NMSO3.

Antiviral Agents↗

PubMed2004

A simple technique for improving camera displacement estimation in eye-in-hand visual servoing.

A simple technique for estimating the camera displacement from point correspondences in eye-in-hand visual servoing is presented. The idea for providing more accurate results than existing methods consists of taking into account that the point correspondences used during the camera motion correspond to stationary spatial points, hence exploiting additional information. This is done by first estimating the object Euclidean structure and then estimating the camera displacement from this estimate.

Algorithms↗

PubMed2004

Signaling through the prostaglandin I2 receptor IP protects against respiratory syncytial virus-induced illness.

The role of prostanoids in modulating respiratory syncytial virus (RSV) infection is unknown. We found that RSV infection in mice increases production of prostaglandin I(2) (PGI(2)). Mice that overexpress PGI(2) synthase selectively in bronchial epithelium are protected against RSV-induced weight loss and have decreased peak viral replication and gamma interferon levels in the lung compared to nontransgenic littermates. In contrast, mice deficient in the PGI(2) receptor IP have exacerbated RSV-induced weight loss with delayed viral clearance and increased levels of gamma interferon in the lung compared to wild-type mice. These results suggest that signaling through IP has antiviral effects while protecting against RSV-induced illness and that PGI(2) is a potential therapeutic target in the treatment of RSV.

6-Ketoprostaglandin F1 alpha↗

PubMed2003

The complex relationship between respiratory syncytial virus and allergy in lung disease.

Epidemiologic studies suggest a strong link between severe respiratory syncytial virus (RSV)-induced bronchiolitis in infancy and allergic disease; however, the mechanisms determining this relationship are currently unknown. In this review article, we summarize data from human clinical studies that explore the association between RSV infection and allergy, some that suggest that RSV bronchiolitis requiring hospitalization leads to an increased incidence of the allergic phenotype and others that suggest that pre-existing allergy is a risk factor for severe RSV bronchiolitis. We also review the published murine models that combine RSV infection and allergic sensitization that attempt to explain the complex relationship between these two factors in regard to lung immunopathology and physiologic dysfunction.

Animals↗

PubMed2002

Hypoxia and nitric oxide treatment confer tolerance to glucose starvation in a 5'-AMP-activated protein kinase-dependent manner.

Hypoxia is a critical event for higher organisms, and cells and tissues react by increasing the oxygen supply by vasodilatation, angiogenesis, and erythropoiesis and maintaining cellular energy by increasing glycolysis and inhibiting anabolic pathways. Stimulation of glycolysis has been regarded as the main response that increases energy production during hypoxia; however, there is an obvious conflict during ischemia, because both the oxygen and glucose supply are insufficient. In this study, we found that exposure of HepG2 cells and normal fibroblasts to hypoxia induces cellular tolerance to glucose starvation. The tolerance induced by hypoxia is dependent on several amino acids, indicating a switch from glucose to amino acids as the energy source. When antisense RNA expression vector for 5'-AMP-activated protein kinase or protein kinase B/Akt was transfected into HepG2 cells, the induction of tolerance to glucose was greatly inhibited, indicating that the tolerance was dependent on 5'-AMP-activated protein kinase and protein kinase B/Akt. Similar tolerance was induced by nitric oxide exposure. The tolerance induced was observed in various cells and may represent a previously unknown physiological response related to hypoxia-preconditioning and tumor progression:austerity.

AMP-Activated Protein Kinases↗

PubMed2002

Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice.

Nonselective cyclooxygenase (COX) inhibition during allergic sensitization with ovalbumin in a murine model leads to an increase in the Type 2 cytokines interleukin-5 (IL-5) and IL-13; however, the effect of selective COX-1 and COX-2 inhibitors on these cytokines is unknown. We found that COX-1 protein was constitutively expressed in lung tissue. Expression of COX-1 protein did not increase with ovalbumin sensitization, but expression of COX-2 protein did. Ovalbumin-sensitized mice treated with either selective COX-1 inhibitor SC58560 (OVA-COX-1 inhibitor) or selective COX-2 inhibitor SC58236 (OVA-COX-2 inhibitor) had significantly greater airway hyperresponsiveness (p < 0.05) and higher levels of IL-13 (p < 0.05) in lung supernatants than did untreated mice that were ovalbumin sensitized (OVA). Lung mRNA levels for the chemokine receptors CCR1 through CCR5 (expressed on eosinophils, basophils, lymphocytes, and dendritic cells) were increased in the OVA-COX-2 inhibitor and OVA-indomethacin groups. We conclude that in the BALB/c mouse, COX inhibition with either a COX-1 or COX-2 inhibitor during allergen sensitization augments production of IL-13 and increases airway hyperresponsiveness.

Animals↗

PubMed2002

5-amino-4-imidazolecarboxamide riboside confers strong tolerance to glucose starvation in a 5'-AMP-activated protein kinase-dependent fashion.

Acadesine, 5-amino-4-imidazolecarboxamide riboside (AICAR), has been claimed to protect the heart, lung, and small intestine against ischemic damage. The biochemical mechanisms of this effect of AICAR are not yet fully understood. To understand the mechanism, we examined the effect of AICAR on glucose starvation, since cellular responses to ischemia could be regarded as a protective response to an insufficient blood supply, cells might display adaptive reactions not only to oxygen deficiency but to nutrient deficiency. AICAR was found to confer strong tolerance to glucose starvation. By using antisense RNA expression vector for alpha subunit of 5'-AMP-activated protein kinase, the effect of AICAR was found to be dependent on 5'-AMP-activated protein kinase containing the alpha2 subunit. The AICAR effect was also dependent on the presence of amino acids, indicating an energy source switch from glucose to amino acids.

AMP-Activated Protein Kinases↗

PubMed2002

Effect of continuous ATP injection on human hemodynamics.

Continuous ATP injection is used clinically for Tl imaging or coronary flow measurement and because the effect on human hemodynamics is unknown, the present study investigated it in 14 patients undergoing heart catheter examination. Continuous ATP injection induced chest symptoms in 13 of the patients and second-degree atrioventricular block in one, but these complications disappeared immediately after the end of ATP infusion. Continuous ATP injection decreased aortic pressure, but increased pulmonary artery pressure, right atrial pressure and pulmonary capillary wedge pressure. ATP increased heart rate, stroke volume and cardiac output, the latter the result of an increase in preload, a decrease in afterload, and the increase in heart rate.

Adenosine↗

PubMed2002

Evaluation of a sentinel surveillance system for influenza, 1995-2000, Kyoto City, Japan.

We compared a municipal sentinel surveillance system for influenza with the Microbial Isolation Surveillance System (MISS) in Kyoto City, Japan. Sensitivity, specificity, and predictive value positive (PVP) of the Influenza Sentinel Surveillance System (ISSS) compared to the MISS were calculated by influenza season and by month. Sensitivity ranged from 80 to 97%, specificity ranged from 55 to 77%, and PVP ranged from 29 to 52% by season (P < 0.001). On the other hand, sensitivity ranged from 86 to 100%, specificity ranged from 38 to 66%, and PVP ranged from 31 to 50% by month (P < 0.001). Specificity was calculated as 93% in November. The sensitivity of ISSS was found to be sufficient regardless of the magnitude of influenza activity. Specificity varied by season, indicating the difficulty of clinically diagnosing other respiratory illnesses. The PVP remained at less than 50% before and after the influenza seasons and it varied year by year. In general, the ISSS is a good surveillance system for monitoring influenza activity.

Disease Outbreaks↗

PubMed2001

Involvement of cathepsin E in exogenous antigen processing in primary cultured murine microglia.

We have attempted to elucidate an involvement of cathepsin E (CE) in major histocompatibility complex class II-mediated antigen presentation by microglia. In primary cultured murine microglia, CE was localized mainly in early endosomes and its expression level was markedly increased upon stimulation with interferon-gamma. Pepstatin A, a specific inhibitor of aspartic proteases, significantly inhibited interleukin-2 production from an OVA-(266-281)-specific T helper cell hybridomas upon stimulation with native OVA presented by interferon-gamma-treated microglia. However, pepstatin A failed to inhibit the presentation of OVA-(266-281) peptide. The possible involvement of CE in the processing of native OVA into antigenic peptide was further substantiated by that digested fragments of native OVA by CE could be recognized by OVA-specific Th cells. Cathepsin D also degraded native OVA into antigenic peptide, whereas microglia prepared from cathepsin D-deficient mice retained an ability for antigen presentation. On the other hand, the requirement for cysteine proteases such as cathepsins S and B in the processing of invariant chain (Ii) was confirmed by immunoblot analyses in the presence of their specific inhibitors. In conclusion, CE is required for the generation of an antigenic epitope from OVA but not for the processing of Ii in microglia.

Animals↗