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Biomedical subjects

Hajime Takizawa

Publications and source records attributed to Hajime Takizawa.

At least 19 recordsLinked to original sources
PubMed2006

Repeated exposure to low-dose diesel exhaust after allergen challenge exaggerates asthmatic responses in mice.

BACKGROUND: In conjunction with allergens, diesel exhaust particles act as an adjuvant to enhance IgE responses, inducing expression of cytokines/chemokines and adhesion molecules, and increasing airway hyper-responsiveness (AHR). As most studies were designed to expose animals to diesel exhaust throughout the periods of both sensitization and allergen challenge, it remains unclear whether diesel exhaust (DE) exposure exaggerates airway responses in asthmatic animals. OBJECTIVE: To study effects of exposure to low-dose DE on AHR and allergic airway inflammation in asthmatic mice. METHODS: BALB/c mice were sensitized by intraperitoneal injection of ovalbumin and challenged by intranasal administration with ovalbumin. They were exposed to low-dose DE for 7 h/day, 5 days/week, for up to 12 weeks. AHR to methacholine was evaluated by whole-body plethysmography as well as bronchoalveolar lavage cell analysis and cytokine gene expression in lungs. RESULTS: Repeated exposure of asthmatic mice to low-dose DE resulted in increased AHR and gene expression of several pro-asthmatic cytokines/chemokines, but these effects rapidly subsided with continued exposure to DE. CONCLUSION: Repeated exposure to low-dose DE after ovalbumin challenge exaggerates allergic responses in mice, but effects are not prolonged with continuous DE exposure.

Allergens↗
PubMed2005

Leukotriene D4 potentiates fibronectin-induced migration of human lung fibroblasts.

Fibroblasts play an important role in the repair and remodeling processes following injury. Leukotriene D4 (LTD4) is a potent mediator in inflammatory processes, but the direct effect of cysteinyl leukotrienes on fibroblast migration remains unelucidated. In this study, the effect of the LTD4 on normal human lung fibroblasts (NHLF) chemotaxis induced by human plasma fibronectin (HFn) was investigated using the modified Boyden's chamber technique. LTD4 potentiated NHLF chemotaxis to HFn in concentration-dependent manner. A specific cysteinyl leukotriene receptor type 1 antagonist, pranlukast inhibited this effect, indicating that LTD4 affected cell migration via its specific receptor. The potentiating effect of LTD4 on fibroblast chemotaxis was completely abolished by pertussis toxin (PTX), suggesting that LTD4-induced effect was dependent on PTX-sensitive Gi/o signaling. These findings suggest that LTD4 has a potential to augment fibroblast chemotaxis, and to contribute to regulation of the wound healing and following remodeling in fibrotic processes of the lung.

Adjuvants, Immunologic↗
PubMed2005

The effects of inhalation of diesel exhaust on murine mycobacterial infection.

The authors investigated the effects of inhalation of diesel exhaust (DE) on murine mycobacterial infection in vivo. Eight-week-old female BALB/c mice were exposed to DE (3 mg/m3 of diesel exhaust particles [DEPs]) for 1 month, 2 months, or 6 months (for 7 hours a day, 5 days a week). Control mice were housed in a clean room for the same periods. On the day following the last DE exposure, control mice and DE-exposed mice were aerially infected with Mycobacterium tuberculosis (1 x 10(6) colony-forming units (CFU), Kurono strain). At 7 weeks after mycobacterial infection, the authors examined the lung tissues for histopathological changes and performed reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the messenger RNA (mRNA) expression of several proinflammatory cytokines and inducible nitric oxide synthase (iNOS). Then, the homogenates of lungs and spleens were cultured on 1% (v/v) Ogawa's egg slant medium, and after a 4-week incubation period at 37 degrees C, colonies on the medium were counted. After 1 month of DE exposure, the mycobacterial infection had slightly ameliorated. After 2 months of DE exposure, the expression levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-12p40, interferon (IFN)-gamma, and iNOS mRNAs were slightly increased. However, after 6 months of DE exposure, the expression levels of IL-1beta , IL-12p40, IFN-gamma, and iNOS mRNAs were decreased, and the infection as measured by increased lung burden (CFU) actually increased. These results indicate that long-term DE exposure may increase pulmonary mycobacterial burden.

Administration, Inhalation↗
PubMed2005

Bronchial epithelial cells in allergic reactions.

Bronchial epithelial cells (BEC) are known to play an integral role in the airway defense mechanism via mucociliary system as well as mechanical barriers. Recent studies further indicate that BEC produce and release biologically active compounds including lipid mediators, growth factors, endothelin and a variety of cytokines/chemokines important in the pathogenesis of airway disorders. Cytokines and chemokines produced by BEC include IL-6, IL-8, G-CSF, GM-CSF, RANTES, eotaxin and TARC. Pro-inflammatory cytokines IL-1 and TNF-alpha, generally upregulate expression and release these cytokines/chemokines. BEC from patients with bronchial asthma showed increased levels of mRNA for these potent inflammatory peptides. BEC also interact with immune and inflammatory cells by direct adhesion as well as by humoral factors including cytokines. For example, eosinophil adhesion to BEC may be an important signal for the activation and degranulation of eosinophils. BEC is also believed to take part in the airway mucosal immunity via Toll-like receptors. Finally, BEC may play a crucial role in the processes of airway remodeling by cross-talk with mesenchymal cells. These findings strongly suggest that BEC are actively involved as regulators of allergic inflammatory responses, and become a target for therapeutic intervention.

Animals↗
PubMed2005

Additive effect of diesel exhaust particulates and ozone on airway hyperresponsiveness and inflammation in a mouse model of asthma.

Allergic airway diseases are related to exposure to atmospheric pollutants, which have been suggested to be one factor in the increasing prevalence of asthma. Little is known about the effect of ozone and diesel exhaust particulates (DEP) on the development or aggravation of asthma. We have used a mouse asthma model to determine the effect of ozone and DEP on airway hyperresponsiveness and inflammation. Methacholine enhanced pause (P(enh)) was measured. Levels of IL-4 and IFN-gamma were quantified in bronchoalveolar lavage fluids by enzyme immunoassays. The OVA-sensitized-challenged and ozone and DEP exposure group had higher P(enh) than the OVA-sensitized-challenged group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone exposure group. Levels of IFN-gamma were decreased in the OVA-sensitized-challenged and DEP exposure group and the OVA-sensitized-challenged and ozone and DEP exposure group compared to the OVA-sensitized-challenged and ozone exposure group. Levels of IL-4 were increased in the OVA-sensitized-challenged and ozone exposure group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone and DEP exposure group compared to OVA-sensitized-challenged group. Co-exposure of ozone and DEP has additive effect on airway hyperresponsiveness by modulation of IL-4 and IFN-gamma suggesting that DEP amplify Th2 immune response.

Air Pollutants↗
PubMed2005

Cytokine responsiveness in cultured human small airway epithelial cells in relation to lung transplantation.

BACKGROUND: We report a new method for collecting and establishing small airway epithelial cells (SAEC). This method enables the evaluation of the cytokine responsiveness of SAEC, which is still unknown. In this study we evaluated intercellular adhesion molecule-1 (ICAM-1) expression on SAEC stimulated with several inflammatory cytokines and compared it with that on large airway epithelial cells (LAEC). MATERIALS AND METHODS: LAEC and SAEC were treated with IFN-gamma, TNF-alpha, IL-1beta, or their combination. ICAM-1 expression under various conditions was quantified by flow cytometry. Furthermore, immunocytochemical staining was performed to determine intranuclear displacement of signal transducer and activator transcription 1 (Stat1) during ICAM-1 expression by various cytokine stimulations. RESULTS: 1) ICAM-1 expression on both LAEC and SAEC was significantly increased by IFN-gamma stimulation alone and synergistically enhanced by IFN-gamma plus TNF-alpha or IL-1beta stimulation, 2) intranuclear displacement of Stat1 in SAEC by the stimulation with IFN-gamma plus TNF-alpha or IL-1beta was recognized earlier in comparison with that by IFN-gamma stimulation alone. CONCLUSION: The previously unknown peripheral cytokine responsiveness and its mechanisms of SAEC were revealed by this study, which contributes to the understanding of chronic lung allograft rejection recognized around small airways.

Adult↗
PubMed2004

Clinical implications of the immunomodulatory effects of macrolides.

Macrolide antibiotics are known for their efficacy in treating acute airway infections, but just as importantly, they are also effective anti-inflammatory agents. Their anti-inflammatory properties have been studied most thoroughly in chronic inflammatory airway diseases, particularly diffuse panbronchiolitis (DPB). Erythromycin, azithromycin, clarithromycin, and roxithromycin inhibit chemotaxis and infiltration of neutrophils into the airway and, subsequently, decrease mucus secretion. Mucus formation, a significant cause of morbidity and mortality in patients with chronic airway inflammation, is directly inhibited by macrolides and suppressed by decreased inflammation in the airway. The mechanisms of action for the anti-inflammatory properties of the macrolides are still being investigated, but they are clearly multifactorial. Macrolides inhibit the production of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha, perhaps by suppressing the transcription factor nuclear factor-kappaB or activator protein-1. Inhibition of cytokine production has been seen in vitro and also in bronchoalveolar lavage fluid, which contains less IL-8 and fewer neutrophils after treatment with macrolides. Macrolides also inhibit formation of leukotriene B4, which attracts neutrophils, and inhibit the release of superoxide anion by neutrophils that may be present in the airway. An important aspect of inflammation is extravasation of neutrophils into the tissues. Macrolides block formation of adhesion molecules necessary for neutrophil migration. Together, these anti-inflammatory effects result in improved pulmonary functions and fewer airway infections. In patients with DPB, the anti-inflammatory effects lead to a significant increase in survival. Further work is needed to characterize the clinical benefits of macrolides in patients with other chronic inflammatory airway diseases.

Anti-Bacterial Agents↗
PubMed2004

A novel snake venom vascular endothelial growth factor (VEGF) predominantly induces vascular permeability through preferential signaling via VEGF receptor-1.

Vascular endothelial growth factor (VEGF)/vascular permeability factor induces both angiogenesis and vascular permeability mainly through VEGF receptor (VEGFR)-2 activation. VEGF binds VEGFR-1 as well, but the importance of VEGFR-1 signaling in vascular permeability has been largely neglected. Here, we report the purification and characterization of a novel VEGF-like protein from Trimeresurus flavoviridis Habu snake venom. The Habu snake has a venom-specific VEGF-like molecule, T. flavoviridis snake venom VEGF (TfsvVEGF), in addition to VEGF-A. TfsvVEGF has almost 10-fold less mitotic activity than VEGF(165), a predominant isoform of human VEGF-A, but a similar effect on vascular permeability. TfsvVEGF bound VEGFR-1 and induced its autophosphorylation to almost the same extent as VEGF(165), but bound VEGFR-2 weakly and induced its autophosphorylation almost 10-fold less effectively than VEGF(165). This unique binding affinity for VEGFR-1 and VEGFR-2 leads to the vascular permeability-dominant activity of TfsvVEGF. These results suggest that Habu snakes have acquired a highly purposive molecule for a toxin, which enhances the toxicity in envenomation without inducing effective angiogenesis and the following regeneration of damaged tissues, taking advantage of the difference in signaling properties involving VEGFR-1 and VEGFR-2 between vascular permeability and angiogenesis. TfsvVEGF is thus a potent inducing factor selective for vascular permeability through preferential signaling via VEGFR-1. These data strongly indicate the importance of VEGFR-1 signaling in vascular permeability.

Amino Acid Sequence↗
PubMed2004

Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A.

Voltage-gated Na(+) channel (I(Na)) is expressed under culture conditions in human smooth muscle cells (hSMCs) such as coronary myocytes. The aim of this study is to clarify the physiological, pharmacological and molecular characteristics of I(Na) expressed in cultured hSMCs obtained from bronchus, main pulmonary and coronary artery. I(Na), was recorded in these hSMCs and inhibited by tetrodotoxin (TTX) with an IC(50) value of approximately 10 nM. Reverse transcriptase/polymerase chain reaction (RT-PCR) analysis of mRNA showed the prominent expression of transcripts for SCN9A, which was consistent with the results of real-time quantitative RT-PCR. These results provide novel evidence that TTX-sensitive Na(+) channel expressed in cultured hSMCs is mainly composed of Na(v)1.7.

Bronchi↗
PubMed2004

Platelet-activating factor receptor develops airway hyperresponsiveness independently of airway inflammation in a murine asthma model.

Lipid mediators play an important role in modulating inflammatory responses. Platelet-activating factor (PAF) is a potent proinflammatory phospholipid with eosinophil chemotactic activity in vitro and in vivo. We show in this study that mice deficient in PAF receptor exhibited significantly reduced airway hyperresponsiveness to muscarinic cholinergic stimulation in an asthma model. However, PAF receptor-deficient mice developed an eosinophilic inflammatory response at a comparable level to that of wild-type mice. These results indicate an important role for PAF receptor, downstream of the eosinophilic inflammatory cascade, in regulating airway responsiveness after sensitization and aeroallergen challenge.

Animals↗
PubMed2004

Methotrexate induces interleukin-8 production by human bronchial and alveolar epithelial cells.

Methotrexate (MTX) has been widely used for the treatment of a variety of tumours as well as for inflammatory diseases. MTX-induced pneumonitis has been a serious unpredictable side effect of the treatment and an important clinical problem. However, its mechanism remains largely unclear. Possible causes include allergic, cytotoxic or immunologic reactions to this agent. To elucidate the proinflammatory mechanism of MTX-induced pneumonitis, we evaluated the effect of MTX on the production of IL (interleukin)-8 by human bronchial and alveolar epithelial cells in vitro and the role of p38 MAPK (mitogen-activated protein kinase) in order to clarify the intracellular signal regulating IL-8 expression. MTX induced IL-8 secretion by human bronchial and alveolar epithelial cells in a dose- and time-dependent manner within the range of the clinically observed serum concentrations. Although addition of LPS (lipopolysaccharide) and glucose showed no significant enhancing effect, addition of IL-1beta or TNF-alpha (tumour necrosis factor-alpha) with MTX to bronchial epithelial cells showed a significant augmenting effect. SB203580, the specific inhibitor of p38 MAPK, inhibited MTX-induced IL-8 production. MTX induced the phosphorylation of Thr(180) and Tyr(182) on p38 MAPK. These results suggest that MTX activates bronchial and alveolar epithelial cells to induce IL-8 production through p38 MAPK, which might play an important role as one of the mechanisms of MTX-induced lung inflammation.

Acetylcysteine↗
PubMed2004

Diesel exhaust particles and their effect on induced cytokine expression in human bronchial epithelial cells.

PURPOSE OF REVIEW: It has been demonstrated that particulate air pollutants such as diesel exhaust particles (DEPs) are associated with allergic respiratory disorders, including asthma and allergic rhinitis. Recent in-vivo and in-vitro studies strongly suggest that DEPs induce both anti-inflammatory and proinflammatory products by activating their transcription. If pollutants are to be controlled in the environment in a cost-effective manner, it is important that the molecular target(s) of DEP-induced responses be elucidated. Bronchial epithelial cells are the key regulators of airway inflammation, and therefore it is crucial to clarify the cellular and molecular mechanisms that are active in these cells. It is also important to compare responses to DEP exposure between healthy and susceptible populations. RECENT FINDINGS: Studies have shown that DEPs activate several signalling pathways such as mitogen-activated protein kinases and transcription factors, in particular nuclear factor-kappa and activator protein-1, in human bronchial epithelial cells; these effects are thought to occur via production of reactive oxygen species. Antioxidants effectively reduce the allergic inflammatory effects of DEPs both in vitro and in mice. SUMMARY: Host responses to DEPs are regulated by a balance between antioxidants and proinflammatory responses. DEP-induced oxidants play a key role in proinflammatory reactions. Recent human studies suggest that chemoprevention against DEP-induced adverse effects in susceptible individuals is possible.

Bronchi↗
PubMed2004

Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation.

Long-term macrolide therapy has been proven to improve survival in patients with diffuse panbronchiolitis. Although its mechanisms remain unknown, previous studies have suggested the effects of macrolide might be anti-inflammatory rather than antibacterial. To elucidate the molecular mechanisms of its action, we studied here the effects of erythromycin (EM) and its new derivative, EM703, which shows no antibacterial action, on the activation of the transcription factor nuclear factor-kappaB (NF-kappaB) in human bronchial epithelial cells. Western blotting analysis showed that EM did not inhibit the degradation of IkappaBalpha, suggesting the molecular target for EM was not the dissociation of NF-kappaB from IkappaB. An electrophoretic mobility shift assay showed that EM did not interrupt the NF-kappaB DNA-binding activity in the nucleus under the conditions tested. Moreover, not only EM but also EM703 suppressed the activation of NF-kappaB and the production of interleukin-8, demonstrating that the anti-inflammatory action of the macrolide is independent of its antibacterial activity. Taken together, these data suggest EM has an anti-inflammatory action, presumably via an interaction with the NF-kappaB signaling pathway in the downstream of the dissociation from IkappaB, resulting in the inhibition of NF-kappaB.

Anti-Bacterial Agents↗
PubMed2004

Alpha-1 antitrypsin deficiency with severe pulmonary emphysema.

Alpha-1 antitrypsin (AAT) deficiency is a hereditary disorder characterized by an early onset of emphysema. While this disease is common in the Caucasian population, it is quite rare in Japan. To date, only 15 traits have been reported and it can be speculated that many cases of this genetic deficiency may have been overlooked. We report an additional case of AAT deficiency with severe emphysema that is genetically determined as S(iiyama) variant by allele-specific polymerase chain reaction (PCR) analysis.

Alleles↗