Mio Kawaguchi

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (87)231.26 Total impact

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    ABSTRACT: Interleukin (IL)-32 is a novel cytokine and is involved in the pathogenesis of various inflammatory diseases, including asthma and COPD. However, the regulatory mechanisms of IL-32 expression and its precise pathogenic role remain to be defined. Given that viral infections are known to potentially cause and exacerbate airway inflammation, in this study, we investigated the expression of IL-32 induced by synthetic double-stranded (ds) RNA, and its signaling mechanisms involved. Bronchial epithelial cells were stimulated with synthetic dsRNA poly I:C. The levels of IL-32 expression were analyzed using real-time PCR and ELISA. The involvement of transforming growth factor β-activated kinase 1 (TAK1) and a subunit of nuclear factor-κB (NF-κB), p65 was determined by western blot analyses. TAK1 inhibitor, 5Z-7-Oxozeaenol and NF-κB inhibitor, BAY 11-7082 were added to the culture to identify key signaling events leading to the expression of IL-32. Finally, the effect of short interfering RNAs (siRNAs) targeting TAK1 and p65 was investigated. dsRNA significantly induced IL-32 gene and protein expression, concomitant with activation of TAK1 and p65. Pretreatment of 5Z-7-Oxozeaenol diminished dsRNA-induced phosphorylation of NF-κB. Both 5Z-7-Oxozeaenol and BAY 11-7082 significantly abrogated dsRNA-induced IL-32 production. Moreover, transfection of the cells with siRNAs targeting TAK1 and p65 inhibited the expression of IL-32. The expression of IL-32 is induced by dsRNA via the TAK1-NF-κB signaling pathway in bronchial epithelial cells. IL-32 is involved in the pathogenesis of airway inflammation, and may be a novel therapeutic target for airway inflammatory diseases.
    Experimental Lung Research 07/2015; DOI:10.3109/01902148.2015.1033569 · 1.75 Impact Factor
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    ABSTRACT: Therapy with crizotinib achieves prolonged progression-free and overall survival in non-small-cell lung cancer (NSCLC) patients with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK). It was demonstrated that ALK-positive NSCLCs exhibit a high response rate to the ALK inhibitor, crizotinib. However, a proportion of the patients discontinue crizotinib treatment due to adverse events. This is the case report of a NSCLC patient with EML4-ALK rearrangement, who, following crizotinib discontinuation for one year due to adverse events, exhibited a marked response to alectinib. Even if the incidence is not high, clinicians should not overlook the most common crizotinib-related adverse events. Furthermore, certain patients may continue to benefit from alectinib following long-term discontinuation of crizotinib therapy.
    Molecular and Clinical Oncology 03/2015; 3(4). DOI:10.3892/mco.2015.531
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    ABSTRACT: Certain internal malignancies, including colon cancer, can develop endobronchial metastasis. The present study reports a case of colon cancer with superficial-type endobronchial metastases in a 76-year-old male. Chest computed tomography revealed small masses and infiltrates in each lung, with bilateral hilar lymph node swelling. Superficial endobronchial tumors in each of the bronchi were unexpectedly found by bronchoscopic examination. A biopsy specimen obtained from the endobronchial tumor was diagnosed as colon cancer. Superficial-type endobronchial metastasis from colon cancer is extremely rare, however, such metastasis should be considered for patients who have a history of colon cancer. There should be no hesitation in performing a bronchoscopic biopsy as an additional examination.
    Oncology letters 11/2014; 8(5):2310-2312. DOI:10.3892/ol.2014.2473 · 0.99 Impact Factor
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    ABSTRACT: Cases of ossification and increased bone mineral density (BMD) at sites of bone metastasis following zoledronic acid (ZA) treatment have not been reported. The current study presents the case of a 65-year-old patient with lung adenocarcinoma and bone metastases in the lumbar vertebrae and femurs. Ossification and an increase in BMD at the metastatic sites was achieved following treatment with ZA and irradiation of the bone metastatic sites. The patient was able to maintain a normal lifestyle for over two years, despite the bone metastases. Therefore, as treatment with ZA was demonstrated to improve patient quality of life, physicians should consider this treatment strategy, particularly for the treatment of metastasis in weight-bearing bones.
    Experimental and therapeutic medicine 10/2014; 8(4):1267-1270. DOI:10.3892/etm.2014.1914 · 0.94 Impact Factor
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    ABSTRACT: Patients with skin metastasis always had disseminated metastases in many organs. We herein report an unusual case with skin metastasis from small cell lung cancer (SCLC). The patient was treated with platinum-containing chemotherapy, and the response to the therapy was evaluated as partial response. The patient had slowly progressive disease and died of SCLC 16 months after the diagnosis of the diseases. If skin lesions, whether it may be typical or not, are found in SCLC patients, biopsy from the lesion would be considered to perform. Although trunk may be the most common sites, it is important to suspect such metastasis occurs in patients with SCLC.
    Tuberkuloz ve toraks 06/2014; 62(2):147-150. DOI:10.5578/tt.6872
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    ABSTRACT: The expression of IL-17F is seen in the airway of asthmatics and its level is correlated with disease severity. Several studies have demonstrated that IL-17F plays a pivotal role in allergic airway inflammation and induces several asthma-related molecules such as CCL20. IL-17F-induced CCL20 may attract Th17 cells into the airway resulting in the recruitment of additional Th17 cells to enhance allergic airway inflammation. We have recently identified, for the first time, that bronchial epithelial cells are its novel cell source in response to IL-33 via ST2-ERK1/2-MSK1 signaling pathway. The receptor for IL-17F is the heterodimeric complex of IL-17RA and IL-17RC, and IL-17F activates many signaling pathways. In a case-control study of 867 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL-17F gene was associated with asthma. In atopic patients with asthma, prebronchodilator baseline FEV1/FVC values showed a significant association with the H161R variant. Moreover, this variant is a natural antagonist for the wild-type IL-17F. Moreover, IL-17F is involved in airway remodeling and steroid resistance. Hence, IL-17F may play an orchestrating role in the pathogenesis of asthma and may provide a valuable therapeutic target for development of novel strategies.
    Journal of Immunology Research 04/2014; 2014:602846. DOI:10.1155/2014/602846 · 2.93 Impact Factor
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    ABSTRACT: The long-term safety of budesonide/formoterol (BUD/FM) inhalation has not been fully evaluated, particularly in elderly patients with bronchial asthma. To evaluate the 12-month safety of BUD/FM inhalation for elderly asthmatic patients, the changes in serum potassium levels and pulse rate were examined. A retrospective chart review was conducted of consecutive patients who were treated with BUD/FM inhalation (two inhalations of 160/4.5 mg, twice daily; Symbicort Turbuhaler, AstraZeneca) at a hospital between February 2010 and January 2012. A total of 350 patients were treated with BUD/FM inhalation during the study period and were followed up over 12 months. The mean age of the patients was 60 years, and 19.4% and 21.4% of the patients were aged 65-74 years and ≥75 years, respectively. One hundred and fourteen (32.6%) of the 350 patients continued the inhalation therapy for >12 months. Compared with the pretreatment data, reductions in serum potassium levels at 1, 6 and 12 months were not observed, even in the patients aged 65-74 and ≥75 years. There was also no increase in the pulse rate at 1, 6 and 12 months, even in the patients aged 65-74 and ≥75 years. The usual dosage of BUD/FM showed no adverse effects on the serum potassium levels and pulse rate in the adults, including the elderly with persistent asthma.
    Experimental and therapeutic medicine 04/2014; 7(4):1005-1009. DOI:10.3892/etm.2014.1515 · 0.94 Impact Factor
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    ABSTRACT: The brain is one of the most common sites of metastasis of small-cell lung cancer (SCLC). In this study, we reported 6 cases with isolated brain relapse of SCLC ≥1 year after the completion of the initial treatment for SCLC. Of the 6 patients, 2 had a solitary brain metastasis and 4 had ≥2 brain metastatic sites. The metastases were identified during a regular check-up computed tomography (CT) scan and were successfully treated. The median interval from the initial diagnosis to the development of brain metastasis was 16 months (range, 13-30 months). All patients received whole-brain irradiation and achieved a complete response. Only one patient developed disturbances of the higher cerebral function. The median interval from whole-brain irradiation to death or last follow-up was 33 months (range, 8-90 months). To the best of our knowledge, these are the first reported cases with isolated brain relapse of SCLC. Although a rare finding, clinicians should be alert on the possibility of such recurrence, particularly in patients who refused prophylactic cranial irradiation.
    Molecular and Clinical Oncology 03/2014; 2(2):305-307. DOI:10.3892/mco.2013.236
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    ABSTRACT: To the best of our knowledge, the formation of a retroperitoneal abscess due to acute appendicitis shortly after administration of chemotherapy for lung cancer has not been previously reported. This is the case report of a 59-year-old male who was admitted to the Mito Medical Center (Mito, Japan) and diagnosed with lung adenocarcinoma with pleuritis carcinomatosis. Although no distant metastasis was identified, combination chemotherapy with cisplatin and pemetrexed was administered. Nine days after initiating chemotherapy, the patient developed right lower quadrant abdominal pain and high fever. Computed tomography (CT) of the abdomen and pelvis revealed the collection of gas and fluid in the retroperitoneum adjacent to the cecum. The abscess was locally drained; however, the infection continued to spread, with subsequent development of a scrotal abscess. Consequently, appendectomy was performed. The patient recovered well and the lung adenocarcinoma was treated with additional courses of chemotherapy following the remission of the local inflammation. Retroperitoneal abscess due to acute appendicitis is an unusual finding; however, this rare complication should be considered during or shortly after chemotherapy in patients with lung cancer.
    Molecular and Clinical Oncology 03/2014; 2(2):302-304. DOI:10.3892/mco.2013.228
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    ABSTRACT: Steroid-insensitive asthma is an infrequent but problematic airway disease that presents with persistent symptoms, airflow limitation, or recurrent exacerbations even when treated with steroid-based therapies. Because of unsatisfactory results obtained from currently available therapies for steroid-insensitive asthma, a better understanding of its pathogenesis and the development of new targeted molecular therapies are warranted. Recent studies indicated that levels of interleukin (IL)-17 are increased and both eosinophils and neutrophils infiltrate the airways of severe asthmatics. IL-17 is a proinflammatory cytokine mainly secreted from helper T (Th) 17 cells and is important for the induction of neutrophil recruitment and migration at sites of inflammation. This review focuses on the pathogenetic role of Th17 cells and their associated cytokines in steroid-insensitive asthma and discusses the prospects of novel therapeutic options targeting the Th17 signaling pathway.
    Clinical and Developmental Immunology 12/2013; 2013:609395. DOI:10.1155/2013/609395 · 2.93 Impact Factor
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    ABSTRACT: The brain is one of the most common sites for the metastasis of small cell lung cancer (SCLC). The present study describes two cases of an isolated solitary brain metastasis as a relapse of SCLC, which occurred more than one year after the completion of the initial successful treatment for SCLC. The tumors were identified during a regular check-up computed tomography (CT) scan and were successfully treated. To the best of our knowledge, this is the first study to report the cases of two patients with an isolated solitary brain metastasis as a relapse of SCLC. Although extremely rare, the possibility of such recurrences should be considered, particularly in patients who have refused prophylactic cranial irradiation.
    Oncology letters 10/2013; 6(4):1108-1110. DOI:10.3892/ol.2013.1489 · 0.99 Impact Factor
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    ABSTRACT: The current study presents a rare case of small cell lung cancer (SCLC) with endobronchial growth in a 68-year-old male. Chest CT scans revealed an ill-defined mass in the upper lobe of the right lung, with ipsilateral mediastinial lymph node swelling. An endobronchial polypoid tumor in the right B3 bronchus was located by bronchoscopic examination. The analysis of a biopsy specimen obtained from the tumor resulted in a diagnosis of SCLC. Although extremely rare, this case highlights the importance of considering a diagnosis of SCLC in patients presenting with a pulmonary tumor adjacent to the bronchus, with an endobronchial polypoid lesion.
    Oncology letters 08/2013; 6(2):553-555. DOI:10.3892/ol.2013.1423 · 0.99 Impact Factor
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    ABSTRACT: The prognosis of carcinomatous peritonitis and meningitis is poor since ascites and focal neurological dysfunctions usually do not improve despite the available treatment options for this devastating disease. This is a case report of peritoneal and meningeal relapse from lung adenocarcinoma following a response to gefitinib. A 72-year-old woman was diagnosed with adenocarcinoma in the upper lobe of the left lung, accompanied by a massive carcinomatous pleural effusion. Following a cisplati-based chemotherapy, gefitinib was initiated, achieving satisfactory disease control. At 8 months after gefitinib initiation, the patient developed abdominal distension, gait disturbance and visual disorder of the right eye. Adenocarcinoma cells were detected in the ascitic and pleural fluids. The findings of this case report suggest that clinicians should remain vigilant for this type of metastasis, although it is rarely encountered.
    Molecular and Clinical Oncology 07/2013; 1(4):785-787. DOI:10.3892/mco.2013.122
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    ABSTRACT: Multipotent mesenchymal stem cells (MSCs) have become a promising therapeutic approach in many clinical conditions. The hypothesis that MSCs can provide a potential therapy for human anti-glomerular basement membrane (GBM) glomerulonephritis (GN) was tested. Nephrotoxic serum nephritis was induced in Wistar-Kyoto rats on day 0. Groups of animals were given either human MSCs (hMSCs, 3×10(6)) or vehicle by intravenous injection on day 4; all rats were sacrificed at either day 7 or day 13. Fluorescently labeled hMSCs were localized in glomeruli and tubulointerstitium 5 h after hMSC administration and persisted until 48 h, but hMSCs were barely detectable after 7 days. hMSC-treated rats had decreased kidney weight, proteinuria, and glomerular tuft area at each time point. The serum creatinine level and degree of glomerular crescent formation were decreased by hMSC treatment on day 13. ED1-positive macrophages, CD8-positive cells, and TUNEL-positive apoptotic cells in glomeruli were reduced by hMSC treatment on day 7, and this trend in apoptotic cells persisted to day 13. Renal cortical mRNA for TNF-α, IL-1β, and IL-17, and the serum IL-17A level were decreased, whereas renal cortical mRNA for IL-4 and Foxp3 and the serum IL-10 level were increased in the MSC-treated group on day 7. Collagen types I and III and TGF-β mRNA were decreased by hMSC treatment on day 13. The present results demonstrated that anti-inflammatory and immunomodulatory effects were involved in the mechanism of attenuating established experimental anti-GBM GN by hMSCs. These results suggest that hMSCs are a promising therapeutic candidate for the treatment of anti-GBM GN.
    PLoS ONE 06/2013; 8(6):e67475. DOI:10.1371/journal.pone.0067475 · 3.53 Impact Factor
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    ABSTRACT: Background: Viral infection can exacerbate asthma by inducing the accumulation of inflammatory cells in the airway. We have previously reported that double-stranded RNA (dsRNA), a viral product and ligand of the Toll-like receptor-3 (TLR3), activates the transcription factors NF-kappa B and IRF-3 and upregulates the expression of inflammatory chemokines in airway epithelial cells. Here, we examined the effects of the glucocorticoid fluticasone propionate (FP) on the expression of the inflammatory chemokines CCL5, CXCL8 and CXCL10. Methods: The airway epithelial cell line BEAS-2B was used for this study. Expression of CCL5, CXCL8 and CXCL10 mRNA and protein was quantified by real-time PCR and ELISA assay, respectively. To examine the association of FP with the physiology of chemokine production, we included several methods. Nuclear translocation of transcription factors was determined by performing Western blot analysis. Histone deacetylase (HDAC) activity in nuclear extracts was measured using a colorimetric assay. Stability of the chemokine mRNAs was examined in cells incubated with actinomycin D. The activities of the CCL5 promoter and the transcription factors NF-kappa B and IRF-3 were assessed using luciferase reporter assays. Results: Treatment of BEAS-2B cells with FP significantly and dose-dependently (10(-9) to 10(-6) M) inhibited dsRNA-induced expression of CCL5, CXCL8 and CXCL10 protein and mRNA, but did not affect mRNA stability. FP also significantly inhibited dsRNA-stimulated CCL5 promoter activity. However, FP had no effect on the activity of HDAC or the nuclear translocation of NF-kappa B and IRF-3. Conclusions: FP inhibits the dsRNA-stimulated expression of inflammatory chemokines in airway epithelial cells. FP may act by inhibiting chemokine transcription through an as yet unidentified mechanism. Copyright (C) 2013 S. Karger AG, Basel
    International Archives of Allergy and Immunology 04/2013; 161(s2):84-92. DOI:10.1159/000350455 · 2.43 Impact Factor
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    ABSTRACT: The purpose of this study was to examine clinical features and treatment modality approaches in patients with chronic obstructive pulmonary disease (COPD), particularly in those aged 80 years and older. Using databases available at Mito Kyodo General Hospital (Japan), the medical records of COPD patients between April 2009 and December 2011 were retrospectively reviewed. The patient population was divided into three age groups; less than 70 years (the <70 age group), between 70-79 years (the 70-79 age group) and 80 years or older (the ≥80 age group). Demographic data, as well as the efficacy and safety of tiotropium, were compared between the three groups. Patients in the ≥80 age group comprised 35.6% of the study population with COPD (n=174). The ≥80 and 70-79 age groups demonstrated a higher proportion of comorbid disease compared with the <70 age group. A subjective improvement of dyspnea on effort as well as no additional adverse effects were observed in the ≥80 age group, similar to the other two age groups. However, higher incidence of acute exacerbation of COPD in patients aged ≥80 years old was found, particularly in those with comorbid disease. The efficacy and safety of tiotropium in COPD patients in the ≥80 age group were almost identical to patients <80 years old, however, physicians must be cautious with acute exacerbation of COPD in the extremely elderly population with comorbid disease.
    Experimental and therapeutic medicine 04/2013; 5(4):997-1000. DOI:10.3892/etm.2013.956 · 0.94 Impact Factor
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    ABSTRACT: In refractory asthma, neutrophils, rather than eosinophils, often predominate in the airways. Neutrophilic airway inflammation appears to be resistant to steroids and may be related to the Th17, rather than the Th2, cytokine milieu. However, the role of GATA-3 and RORγt, transcription factors for Th2 and Th17 cell differentiation, respectively, in the pathogenesis of steroid-insensitive asthma remains unclear. To examine the effect of GATA-3- and RORγt-overexpression backgrounds on airway inflammation and steroid sensitivity, we generated two strains of transgenic mice overexpressing GATA-3 or RORγt. Mice were sensitized and challenged with OVA. Some OVA-sensitized/challenged mice were treated with dexamethasone, anti-IL-17 Ab, CXCR2 antagonist, or anti-IL-6R Ab to demonstrate their therapeutic effects on airway inflammation. Although Ag-specific airway inflammation and hyperresponsiveness were induced in each mouse, the phenotype of inflammation showed a distinct difference that was dependent upon the genotype. GATA-3-overexpressing mice exhibited steroid-sensitive eosinophilic inflammation with goblet cell hyperplasia and mucus hyperproduction under Th2-biased conditions, and RORγt-overexpressing mice developed steroid-insensitive neutrophilic inflammation under Th17-biased conditions. The levels of keratinocyte-derived chemokine, MIP-2, IL-6, and other neutrophil chemotaxis-related mediators were significantly elevated in OVA-exposed RORγt-overexpressing mice compared with wild-type mice. Interestingly, airway hyperresponsiveness accompanied by neutrophilic airway inflammation in RORγt-overexpressing mice was effectively suppressed by anti-IL-17 Ab, CXCR2 antagonist, or anti-IL-6R Ab administration. In conclusion, our results suggest that the expression levels of GATA-3 and RORγt may be important for determining the phenotype of asthmatic airway inflammation. Furthermore, blockade of the Th17-signaling pathway may be a treatment option for steroid-insensitive asthma.
    The Journal of Immunology 01/2013; 190(3). DOI:10.4049/jimmunol.1202386 · 5.36 Impact Factor
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    ABSTRACT: We herein report the case of a 39-year-old man with recurrent asthma exacerbations preceded by abdominal cramps with the urge to defecate. The patient had a history of near-fatal asthma associated with these gastrointestinal symptoms starting five years before his admission. He stated that, even when his daily asthma symptoms were under control, he suffered from attacks, especially when he had a strong urge to defecate. Although the contribution of increased parasympathetic tone to the onset of bronchospasms was likely, anticholinergics were not effective. Instead, the patient's symptoms successfully improved following the prophylactic use of laxatives, which might therefore be an appropriate therapeutic option for this type of asthma.
    Internal Medicine 01/2013; 52(6):685-7. DOI:10.2169/internalmedicine.52.8943 · 0.97 Impact Factor
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    ABSTRACT: Background: Interleukin (IL)-33, a new member of the IL-1 cytokine family, is involved in T helper (Th) 2-type responses in a wide range of diseases and is mediated by expression of the ST2 receptor in many immune cells. As the effects of IL-33 on dendritic cells (DCs) remain controversial, we investigated the ability of IL-33 to modulate the functions of these cells. Methods: DCs were derived from mouse bone marrow, and the expression of the IL-33 receptor ST2 was examined by fluorescence-activated cell sorting and RT-PCR. The responses of the DCs to IL-33 were examined by RT-PCR and ELISA, and activation of mitogen-activated protein kinases (MAPKs) was determined by Western blotting. Results: ST2 ligand mRNA and protein were detectable in DCs. IL-33 induced the production of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 and the activation of extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase and p38 MAPK. Conclusions: DCs respond directly to IL-33 through ST2. The interaction between IL-33 and DCs may represent a new pathway to initiate Th2-type immune responses. IL-33 and ST2 may play important roles in allergic inflammation. Copyright (C) 2013 S. Karger AG, Basel
    International Archives of Allergy and Immunology 01/2013; 161(s2):52-57. DOI:10.1159/000350363 · 2.43 Impact Factor
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    ABSTRACT: A 69-year-old man, who underwent total thymectomy 5 years previously, was referred to our division because the chest radiograph revealed abnormal shadows in both the lungs. The chest radiograph and CT scan showed pleural thickening in both apexes and tree-in-bud signs in both the lower lobes, which suggested bronchiolitis. We had retrospectively confirmed similar centrilobular small nodules and tree-in-bud signs on the chest CT scan when the thymoma was diagnosed. Mycobacterium intracellulare was detected in the sputum by acid-fast staining and polymerase chain reaction. The coincidence of thymoma and Mycobacterium intracellulare infection appeared to be incidental. Thus, in patients with thymoma, clinicians should carefully evaluate the lung parenchyma as well as the mediastinum on the chest radiograph to identify occult diseases, including Mycobacterium intracellulare infections.
    Kekkaku: [Tuberculosis] 11/2012; 87(11):701-5.

Publication Stats

1k Citations
231.26 Total Impact Points

Institutions

  • 2008–2014
    • University of Tsukuba
      • • Institute of Clinical Medicine
      • • Department of Neurology
      Tsukuba, Ibaraki, Japan
  • 2004–2009
    • Showa University
      • Department of Internal Medicine
      Shinagawa, Tōkyō, Japan
  • 2001–2008
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States