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Masanori Sawada,
Tomotaka Kawayama,
Haruki Imaoka,
Yuki Sakazaki,
Hanako Oda,
Shin-Ichi Takenaka,
Yoichiro Kaku,
Koichi Azuma,
Morihiro Tajiri,
Nobutaka Edakuni,
Masaki Okamoto, Seiya Kato,
Tomoaki Hoshino
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ABSTRACT: IL-18 plays a key role in the pathogenesis of pulmonary inflammatory diseases including pulmonary infection, pulmonary fibrosis, lung injury and chronic obstructive pulmonary disease (COPD). However, it is unknown whether IL-18 plays any role in the pathogenesis of asthma. We hypothesized that overexpression of mature IL-18 protein in the lungs may exacerbate disease activities of asthma. We established lung-specific IL-18 transgenic mice on a Balb/c genetic background. Female mice sensitized- and challenged- with antigen (ovalbumin) were used as a mouse asthma model. Pulmonary inflammation and emphysema were not observed in the lungs of naïve transgenic mice. However, airway hyperresponsiveness and airway inflammatory cells accompanied with CD4(+) T cells, CD8(+) T cells, eosinophils, neutrophils, and macrophages were significantly increased in ovalbumin-sensitized and challenged transgenic mice, as compared to wild type Balb/c mice. We also demonstrate that IL-18 induces IFN-γ, IL-13, and eotaxin in the lungs of ovalbumin-sensitized and challenged transgenic mice along with an increase in IL-13 producing CD4(+) T cells. Treatment with anti-CD4 monoclonal antibody or deletion of the IL-13 gene improves ovalbumin-induced airway hyperresponsiveness and reduces airway inflammatory cells in transgenic mice. Overexpressing the IL-18 protein in the lungs induces type 1 and type 2 cytokines and airway inflammation, and results in increasing airway hyperresponsiveness via CD4(+) T cells and IL-13 in asthma.
PLoS ONE 01/2013; 8(1):e54623. · 4.09 Impact Factor
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Journal of Emergency Medicine 12/2012; 43(6):e489-90. · 1.31 Impact Factor
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ABSTRACT: The proinflammatory cytokine interleukin (IL)-18 was originally discovered as an interferon-γ-inducing factor in 1995. IL-18 is known to play an important role in Th1/Tc1 polarization and promoting the production of Th2 cytokines (e.g., IL-4, IL-5, IL-9, and IL-13) by T cells, NK cells, basophils, and mast cells. IL-18 can act as a cofactor for Th2 cell development and IgE production, and also plays an important role in the differentiation of Th17 cells. IL-18 is a key player in the pathogenesis of inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, adult-onset Still's disease, Sjögren's syndrome, and inflammatory bowel diseases. Furthermore, many lines of evidence suggest that IL-18 plays a key role in the pathogenesis of pulmonary inflammatory diseases, including bronchial asthma and chronic obstructive pulmonary disease. Here, we review the pathological roles of IL-18 in pulmonary inflammatory diseases.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 08/2012; 32(10):443-9. · 1.63 Impact Factor
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Yuki Sakazaki,
Tomoaki Hoshino,
Satoko Takei,
Masanori Sawada,
Hanako Oda,
Shin-ichi Takenaka,
Haruki Imaoka,
Kazuko Matsunaga,
Toshio Ota,
Yuzuru Abe,
Ichiro Miki,
Kiminori Fujimoto,
Tomotaka Kawayama, Seiya Kato,
Hisamichi Aizawa
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ABSTRACT: We analyzed the lung mRNA expression profiles of a murine model of COPD developed using a lung-specific IL-18-transgenic mouse. In this transgenic mouse, the expression of 608 genes was found to vary more than 2-fold in comparison with control WT mice, and was clustered into 4 groups. The expression of 140 genes was constitutively increased at all ages, 215 genes increased gradually with aging, 171 genes decreased gradually with aging, and 82 genes decreased temporarily at 9 weeks of age. Interestingly, the levels of mRNA for the chitinase-related genes chitinase 3-like 1 (Chi3l1), Chi3l3, and acidic mammalian chitinase (AMCase) were significantly higher in the lungs of transgenic mice than in control mice. The level of Chi3l1 protein increased significantly with aging in the lungs and sera of IL-18 transgenic, but not WT mice. Previous studies have suggested Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. However, IL-13 gene deletion did not reduce the level of Chi3l1 protein in the lungs of IL-18 transgenic mice. Based on our murine model gene expression data, we analyzed the protein level of YKL-40, the human homolog of Chi3l1, in sera of smokers and COPD patients. Sixteen COPD patients had undergone high resolution computed tomography (HRCT) examination. Emphysema was assessed by using a density mask with a cutoff of -950 Hounsfield units to calculate the low-attenuation area percentage (LAA%). We observed significantly higher serum levels in samples from 28 smokers and 45 COPD patients compared to 30 non-smokers. In COPD patients, there was a significant negative correlation between serum level of YKL-40 and %FEV(1). Moreover, there was a significant positive correlation between the serum levels of YKL-40 and LAA% in COPD patients. Thus our results suggest that chitinase-related genes may play an important role in establishing pulmonary inflammation and emphysematous changes in smokers and COPD patients.
PLoS ONE 01/2011; 6(9):e24177. · 4.09 Impact Factor
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ABSTRACT: "Adenocarcinoma, mixed subtype" is the most common histologic subtype of lung adenocarcinomas in the World Health Organization classification of 2004. For small peripheral adenocarcinomas, for example, those measuring 2 cm or less in greatest diameter, invasive areas can present various histologic patterns. The purpose of this study is to present the radiologic features of small peripheral lung adenocarcinomas with or without a bronchioloalveolar component and with or without invasive areas, in comparison with histopathologic findings. For this purpose, a detailed evaluation of the characteristics of solid regions in ground-glass opacity on high-resolution computerized tomographic images of lung adenocarcinoma is useful.
Journal of thoracic imaging 05/2010; 26(1):74-81. · 1.42 Impact Factor
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ABSTRACT: We report a case of recurrent mitral regurgitation due to calcification of the expanded polytetrafluoroethylene sutures. According to pathologic findings, it was believed that due to the dystrophic calcification of the fibrous tissue covering the expanded polytetrafluoroethylene sutures, there was increased hyalinization, leading to sclerosis and shortening of the chordae. Calcification of expanded polytetrafluoroethylene sutures after mitral valve repair is a rare complication; however, careful follow-up should be needed because such change may occur in long-term periods after implantation.
The Annals of thoracic surgery 03/2010; 89(3):955-7. · 3.74 Impact Factor
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ABSTRACT: Although mitral stenosis (MS) due to pannus overgrowth after mitral valve repair for rheumatic mitral regurgitation (MR) is not uncommon, it is extremely rare in relation to non-rheumatic mitral regurgitation. Whilst it has been suggested that the rigid annuloplasty ring induces pannus overgrowth in the same manner as the flexible ring, to date only in cases using the flexible ring has pannus formation been confirmed by a pathological examination after redo surgery. The case is described of a woman who had undergone mitral valve repair using a 28 mm rigid ring three years previously because of non-rheumatic MR, and subsequently suffered from MS due to pannus formation over the annuloplasty ring. To the present authors' knowledge, this is the first report of MS due to pannus formation after mitral valve repair using a rigid annuloplasty ring to treat non-rheumatic MR documented at reoperation.
The Journal of heart valve disease 03/2010; 19(2):257-9. · 0.81 Impact Factor
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Yasuhiro Iwata,
Masaki Okamoto,
Tomoaki Hoshino,
Yasuhiko Kitasato,
Yuki Sakazaki,
Morihiro Tajiri,
Kazuko Matsunaga,
Koichi Azuma,
Tomotaka Kawayama,
Takashi Kinoshita,
Haruki Imaoka,
Kiminori Fujimoto, Seiya Kato,
Hirohisa Yano,
Hisamichi Aizawa
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ABSTRACT: Oxidant stress is thought to be involved in the establishment of idiopathic interstitial pneumonia (IIP). Thioredoxin 1 (TRX1) plays a role as a strong antioxidant in vivo, suggesting that TRX1 may be involved in the pathogenesis of IIPs. However, there is no report on TRX1 levels in the sera of IIPs. In addition, TRX1 expression in the lungs of non-specific interstitial pneumonia (NSIP) and cryptogenic organizing pneumonia (COP) patients also has not been reported. Here, we investigated whether or not TRX1 levels are altered in the lungs and sera of patients with idiopathic pulmonary fibrosis (IPF), NSIP, and COP.
Immunohistochemical analysis was performed to examine the expression of TRX1. TRX1 levels in sera were measured using an ELISA kit.
TRX1 was expressed in the bronchiole-alveolar epithelium, especially with regenerative or metaplastic feature, and in alveolar macrophages in usual interstitial pneumonia (UIP) and fibrotic NSIP. TRX1 was weakly expressed in the lungs of cellular NSIP and COP. TRX1 producing cells in UIP (n=16), fibrotic NSIP (n=15), cellular NSIP (n=4), and COP (n=5) were significantly increased when compared to nonsmokers (n=7). TRX1 producing cells in UIP and fibrotic NSIP were significantly increased when compared to cellular NSIP and COP. TRX1 levels in the sera of the patients with IPF (n=32; 74.2 ± 7.5 ng/mL), fibrotic NSIP (n=7; 82.5 ± 18.4 ng/mL), cellular NSIP (n=3; 62.2 ± 3.2 ng/mL) and COP (n=17; 88.8 ± 19.7 ng/mL) were significantly higher than those of control subjects (n=74; 35.3 ± 2.7 ng/mL). Furthermore, TRX1 levels in the sera of IPF patients who later showed acute exacerbation (n=7; 106.6 ± 16.3 ng/mL) were significantly higher than those of IPF patients without acute exacerbation (n=25; 65.1 ± 7.6 ng/mL).
Overproduction of TRX1 in the lungs and sera may play an important role in the pathogenesis of IIPs.
Internal Medicine 01/2010; 49(22):2393-400. · 0.94 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) are the pluripotent cells, which enter the circulation and home to sites of tissue injury or inflammation. MSCs are highlighted as a potential cell vector for gene therapy. In this study, we investigated whether transplanted allogeneic MSCs preferentially accumulate in the lung in rats with pulmonary hypertension (PH) and if so to determine the efficacy of MSC-based prostacyclin synthase (PCS) gene therapy for PH. PH was induced in Lewis rats by injecting monocrotaline at 7-weeks-old (week 0). MSCs were obtained by culturing bone marrow mononuclear cells. Allogeneic MSCs were intravenously transplanted at week 2 when moderate PH had been established. PH enhanced indium-111-oxine-labeled MSC accumulation in the lungs, but not in other organs, 2.5-times and 6-times, 1 and 14 days after transplantation, respectively. Transplantation of MSCs transduced with PCS (PSC-MSCs), but not with GFP (GFP-MSCs), reduced PH, pulmonary arterial thickening, and RV hypertrophy at week 4. The lung prostacyclin production was impaired in PH rats, which was restored and maintained for long time by PCS-MSCs, but not by GFP-MSCs. The survival rate at week 7 was 100% in PCS-MSC-transplanted PH rats, whereas they were 38 and 44% in PH rats and GFP-MSC-transplanted PH rats, respectively. In conclusion, the gene-engineered MSCs would be a suitable cell vector for gene delivery specifically to the PH lung. The allogeneic PCS-MSC transplantation attenuated PH and cardiovascular remodeling, and improved the prognosis in PH rats. The MSC-based PCS gene therapy may be a promising strategy for PH treatment.
Archiv für Kreislaufforschung 10/2009; 105(3):409-17. · 7.35 Impact Factor
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Hiroshi Kudo,
Hisashi Kai,
Hidemi Kajimoto,
Mitsuhisa Koga,
Narimasa Takayama,
Takahiro Mori,
Ayami Ikeda,
Suguru Yasuoka,
Takahiro Anegawa,
Hiroharu Mifune, Seiya Kato,
Yoshitaka Hirooka,
Tsutomu Imaizumi
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ABSTRACT: Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.
Hypertension 09/2009; 54(4):832-8. · 6.21 Impact Factor
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ABSTRACT: Goblet cell hyperplasia with mucus hypersecretion contribute to increased morbidity and mortality in bronchial asthma. We have reported that thioredoxin 1 (TRX1), a redox (reduction/oxidation)-active protein acting as a strong antioxidant, inhibits pulmonary eosinophilic inflammation and production of chemokines and Th2 cytokines in the lungs, thus decreasing airway hyperresponsiveness (AHR) and airway remodeling in mouse asthma models. In the present study, we investigated whether endogenous or exogenous TRX1 inhibits goblet cell hyperplasia in a mouse asthma model involving chronic exposure to antigen.
We used wild-type Balb/c mice and Balb/c background human TRX1-transgenic mice constitutively overproducing human TRX1 protein in the lungs. Mice were sensitized 7 times (days 0 to 12) and then challenged 9 times with ovalbumin (OVA) (days 19 to 45). Every second day from days 18 to 44 (14 times) or days 35 to 45 (6 times), Balb/c mice were treated with 40 microg recombinant human TRX1 (rhTRX1) protein. Goblet cells in the lungs were examined quantitatively on day 34 or 45.
Goblet cell hyperplasia was significantly prevented in TRX1-transgenic mice in comparison with TRX1 transgene-negative mice. rhTRX1 administration during OVA challenge (days 18 to 44) significantly inhibited goblet cell hyperplasia in OVA-sensitized and -challenged wild-type mice. Moreover, rhTRX1 administration after the establishment of goblet cell hyperplasia (days 35 to 45) also significantly ameliorated goblet cell hyperplasia in OVA-sensitized and -challenged wild-type mice.
Our results suggest that TRX1 prevents the development of goblet cell hyperplasia, and also ameliorates established goblet cell hyperplasia.
Allergology International 07/2009; 58(3):403-10.
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ABSTRACT: Administration of several chemotherapeutic drugs, such as bleomycin, busulfan, and gefitinib, often induces lethal lung injury. However, the precise mechanisms responsible for this drug-induced lung injury are still unclear. In the present study, we examined the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury. We performed immunohistochemical analysis of IL-18 and IL-18 receptor (R) alpha chain expression in the lungs of five patients with bleomycin-induced lethal lung injury. Enhanced expression of both IL-18 and IL-18Ralpha was observed in the lungs of all five patients with bleomycin-induced lung injury. To support the data obtained from patient samples, the levels of IL-1beta and IL-18 mRNA and protein, pulmonary inflammation, and lung fibrosis were examined in mouse models of bleomycin-induced lung injury. Intravenous administration of bleomycin induced the expression of IL-1beta and IL-18 in the serum and lungs of wild-type C57BL/6 mice. IL-18-producing F4/80(+) neutrophils, but not CD3(+) T cells, were greatly increased in the lungs of treated mice. Moreover, bleomycin-induced lung injury was significantly attenuated in caspase-1(-/-), IL-18(-/-), and IL-18Ralpha(-/-) mice in comparison with control mice. Thus, our results provide evidence for an important role of IL-1beta and IL-18 in chemotherapy-induced lung injury.
American Journal of Respiratory Cell and Molecular Biology 04/2009; 41(6):661-70. · 5.13 Impact Factor
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ABSTRACT: A Carpentier-Edwards pericardial (CEP) bioprosthesis was explanted from an 81-year-old woman due to nonstructural dysfunction 9 years after mitral valve replacement. The nonstructural dysfunction produced severe regurgitation in the mitral position. During the surgery, excessive pannus overgrowth was seen on the left ventricular side of the CEP bioprosthesis. Pannus overgrowth was prominent on one leaflet. That leaflet was stiff and shortened due to the excessive overgrowth of pannus. In this patient, the distortion of one leaflet was the main reason for transvalvular leakage of the CEP bioprosthesis in the mitral position. A new CEP bioprosthesis was implanted in the mitral position. Pathological analysis revealed fibrotic pannus with a small amount of cellular material over the leaflets of the resected CEP valve. This change was marked on the distorted leaflet.
Journal of Artificial Organs 02/2009; 12(1):55-7. · 1.59 Impact Factor
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Masaki Okamoto,
Koichi Azuma,
Tomoaki Hoshino,
Haruki Imaoka,
Jiro Ikeda,
Takashi Kinoshita,
Shinzo Takamori,
Koichi Ohshima,
Nobutaka Edakuni, Seiya Kato,
Tomoaki Iwanaga,
Hisamichi Aizawa
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ABSTRACT: Previous studies have reported that serum IL-18 levels are increased in some cancers. We investigated whether IL-18 production is increased in sera and cancer cells of patients with non-small cell lung cancer (NSCLC).
Serum levels of IFN-gamma and IL-18 and thioredoxin 1 (TRX1) were measured in 79 patients (51 males, 28 females, median age 67 years) with advanced NSCLC (57 adenocarcinoma, 22 squamous cell carcinoma; TNM stages IIIA [n=11], IIIB [n=24], and IV [n=44]) and 75 healthy age-matched controls (44 males, 31 females, median age 65 years) by enzyme-linked immunosorbent assay. We examined IL-18 production in the lungs and sites of bone metastasis of adenocarcinoma by immunohistochemistry.
Serum IL-18, IFN-gamma, and TRX1 levels in NSCLC patients were significantly (p<0.0001, p=0.0031, and p<0.0001, respectively) higher than in control subjects, while serum IFN-gamma levels in NSCLC were slightly increased. Serum IL-18, but not IFN-gamma or TRX1, levels were significantly (p=0.0102) and negatively associated with overall survival in NSCLC. The serum IL-18 level was identified as an independent prognostic factor for overall survival in multivariate survival analysis. Moreover, serum IL-18 levels were significantly (p=0.049) higher in NSCLC with bone metastasis than in NSCLC without bone metastasis. Based on immunohistochemistry, we observed that cancer cells in the lungs and bone metastases markedly produced IL-18.
Our results suggest that elevated serum IL-18 levels may be associated with IL-18 producing cancer cells in advanced NSCLC.
Internal Medicine 02/2009; 48(10):763-73. · 0.94 Impact Factor
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ABSTRACT: According to current World Health Organization (WHO) criteria, counting mitotic figures (MF), which is equal to the mitotic index (MI), on paraffin sections stained with hematoxylin and eosin (HE) is one of the recognized classification methods for meningiomas. However, it is not always easy to find the area of highest mitotic activity, and there are different perspectives among pathologists with regard to differentiating MF from non-MF, i.e., which are apoptotic figures and which are crushed or distorted cells. Moreover, there is an issue of overgrading in meningiomas with preoperative feeder embolization. Recently, anti-phosphohistone-H3 (PHH3) antibody has been reported as a mitosis-specific marker for meningioma grading. In this study, we attempted PHH3 immunostaining for our meningioma cases and verified not only the sensitivity of PHH3 immunostaining but also that of its usefulness in grading meningiomas. Forty-five initial histologically confirmed meningiomas (37 benign, 7 atypical, and 1 anaplastic) were reviewed according to current WHO criteria based on counting MF on HE-stained slides. PHH3-immunostained MF were counted in the same way, and the MIB-1 labeling index (LI) was calculated for each sample. PHH3-labeled MF were easily identified and permitted rapid recognition of the areas of highest mitotic activity. As a result, significant increase of PHH3 mitotic index (PHH3-MI) in comparison with HE mitotic index (HE-MI) and strong correlations with HE-MI to PHH3-MI as well as PHH3-MI to MIB-1 LI were demonstrated. Furthermore, no significant differences of PHH3-MI between cases with and without feeder embolization were demonstrated. As such, PHH3 may be a sensitive and useful marker for meningioma grading as based on the MF.
Brain Tumor Pathology 01/2009; 26(2):51-7. · 1.19 Impact Factor
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Ryo Shibata,
Seiji Ueda,
Sho-Ichi Yamagishi,
Yusuke Kaida,
Yuriko Matsumoto,
Kei Fukami,
Ayako Hayashida,
Hidehiro Matsuoka, Seiya Kato,
Masumi Kimoto,
Seiya Okuda
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ABSTRACT: Decreased peritubular capillary (PTC) flow due to impaired endothelial function elicits tubulointerstitial ischaemia, thereby enhancing renal damage in chronic kidney disease, including diabetic nephropathy. Since nitric oxide (NO) is a vasodilator and known to play an important role in the maintenance of PTC flow, it is conceivable that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may cause tubulointerstitial ischaemia, thus being involved in the progression of diabetic nephropathy. In this study, we investigated whether overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that degrades ADMA, could improve tubulointerstitial ischaemia in streptozotocin (STZ)-induced diabetic rats.
Recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ) was intravenously administrated to diabetic rats. Three days after the treatment, effects of DDAH overexpression on plasma or urinary levels of ADMA or NO metabolites (NOx), tubulointerstitial ischaemia and renal expression of transforming growth factor-beta (TGF-beta) were evaluated.
Renal DDAH expression and activity were reduced in diabetic rats. Urinary levels of ADMA and TGF-beta were increased, while NOx levels were decreased in diabetic rats. Compared with control rats, pimonidazole-detected hypoxic areas were larger in the kidney of diabetic rats, although the number of capillaries in tubulointerstitial regions was not different between the two groups. In addition, renal expression levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and TGF-beta were also increased in diabetic rats. DDAH overexpression significantly inhibited the increase of ADMA and the decrease of NOx and subsequently decreased urinary albumin excretion levels and ameliorated tubulointerstitial hypoxia and HIF-1alpha as well as TGF-beta expression in diabetic rats.
The present study demonstrated for the first time that the suppression of ADMA by DDAH overexpression could improve tubulointerstitial ischaemia and subsequent renal damage in experimental diabetic nephropathy. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of early diabetic nephropathy.
Nephrology Dialysis Transplantation 12/2008; 24(4):1162-9. · 3.40 Impact Factor
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ABSTRACT: The cell survival activity of human glioma cells is largely dependent on autocrine fibroblast growth factor (FGF) signaling. Caspases, a family of cysteine proteases, play an integral part in the execution phase of apoptosis. To better understand the mechanism of resistance to apoptosis in human glioma cells, we investigated the effect of a blockade of endogenous FGF signaling through the expression of the dominant negative type I FGF receptor (DNFGFR) in U251MG cells. The cells were infected with adenovirus vector expressing DNFGFR (AdDNFGFR) and apoptosis was semi-quantified by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) method and flow cytometric annexin V assay. The activation of caspase-3, -8, and -9, the activation of Akt, a serine/threonine protein kinase, and the cleavage of poly(ADP-ribose) polymerase (PARP) were analyzed by immunoblotting. The infection with AdDNFGFR (multiplicity of infection of 200) induced marked apoptosis, along with a down-regulation of akt phosphorylation, and activation of caspase-9 and -3, but not -8. By contrast, LacZ virus (a control) had minimal effects. The level of the cleaved form of PARP was increased in a time-dependent fashion, and this increase was inhibited by adding Z-DEVD-FMK, a caspase-3 inhibitor, and Z-LEHD-FMK, a caspase-9 inhibitor. Moreover, ultraviolet exposure (100 J/m(2)) induced apoptosis and caspase-8, but not caspase-9, activation. Our data suggested that the induction of apoptosis through the inhibition of endogenous FGF signaling is caspase-9 pathway- dependent. The suppression of this or other specific anti-apoptotic pathways may lead to genetic or pharmacological manipulations that favorably modulate the malignant behavior of human gliomas.
International Journal of Oncology 03/2008; 32(2):467-73. · 2.40 Impact Factor
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ABSTRACT: We herein report an extremely rare case of a patient with IgD-lambda positive multiple myeloma presenting with myelomatous pleural effusion and ascites. A 58-year-old man visited our hospital with dyspnea as his initial symptom. His chest radiograph findings on admission revealed a left pleural effusion, and later, bilateral involvement. Computed tomography (CT) of the chest showed a paraspinal tumor with extension from the upper mediastinum to the abdomen. The cytological examination demonstrated myeloma cells in the pleural effusion and ascites, and histologically, in the pleura, an abdominal subcutaneous tumor and bone was observed. The pleural effusion was an exudate and slightly bloody. The ADA was 70 IU/L. Pleural effusion accompanying myeloma or primary pleural myeloma is very rare and, furthermore, the extremely rare findings of both myeloma cells in the ascites (although the ascites was mainly caused by liver cirrhosis) and a high ADA activity in the pleural fluid were also observed in this case.
Internal Medicine 02/2008; 47(21):1917-20. · 0.94 Impact Factor
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Haruki Imaoka,
Tomoaki Hoshino,
Satoko Takei,
Yuki Sakazaki,
Takashi Kinoshita,
Masaki Okamoto,
Tomotaka Kawayama,
Junji Yodoi, Seiya Kato,
Tomoaki Iwanaga,
Hisamichi Aizawa
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ABSTRACT: The development and treatment of asthma remains a subject of considerable interest in the medical community. Previous studies implicate an important role of cytokines in the pathology of asthma. In this current study, we examined whether redox-active protein thioredoxin 1 (TRX1) could prevent airway remodeling in an ovalbumin (OVA)-driven mouse chronic antigen exposure asthma model. Balb/c mice were sensitized and then challenged nine times with OVA (days 19-45). In this protocol, airway remodeling was established by day 34. Administration of recombinant human TRX1 during antigen challenge (days 18-32) significantly inhibited airway remodeling, eosinophilic pulmonary inflammation, airway hyperresponsiveness and resulted in decreased lung expression of eotaxin, macrophage inflammatory protein-1alpha and IL-13. Airway remodeling and eosinophilic pulmonary inflammation was also prevented in chronic OVA-exposed Balb/c human TRX1 transgenic mice. Importantly, TRX1-administration, after the establishment of airway remodeling (days 35-45), resulted in improved airway pathology. Our results suggest TRX1 prevents the development of airway remodeling, and also improves established airway remodeling by inhibiting production of chemokines and Th2 cytokines in the lungs.
Biochemical and Biophysical Research Communications 09/2007; 360(3):525-30. · 2.48 Impact Factor
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ABSTRACT: To review the high-resolution computed tomography (CT) and histologic findings of acute exacerbation of chronic interstitial pneumonia and to assess the potential value of CT and histologic findings in predicting prognosis.
The study included 24 patients with clinical and histologic diagnosis of acute exacerbation of chronic interstitial pneumonia who underwent CT within 1 month before biopsy or autopsy. The final diagnosis was acute exacerbation of idiopathic pulmonary fibrosis (n=12), usual interstitial pneumonia associated with connective tissue disorders (n=5), idiopathic nonspecific interstitial pneumonia (n=4), and nonspecific interstitial pneumonia associated with connective tissue disorders (n=3).
The main CT findings consisted of bilateral ground-glass opacities (100%) and consolidation (71%) superimposed on a reticular pattern. The ground-glass opacities and/or consolidation were diffuse in 54% of the cases, multifocal in 21%, and peripheral in 25%. The histologic patterns of acute injury consisted of diffuse alveolar damage (n=20), acute organizing pneumonia (OP) (n=3), and extensive fibroblastic foci (n=1). Eight (33%) patients survived the acute episode, including all 3 patients with OP and the patient with extensive fibroblastic foci (P=0.01). The survivors included 3 of 13 (23%) patients with diffuse parenchymal opacification, 2 of 5 (40%) patients with multifocal, and 3 of 6 (50%) patients with peripheral opacification on CT.
The CT findings of acute exacerbation of chronic interstitial pneumonia consist of diffuse, multifocal, or peripheral parenchymal opacification superimposed on reticulation. Histologic findings of OP are superior to CT in predicting prognosis.
Journal of Thoracic Imaging 09/2007; 22(3):221-9. · 0.98 Impact Factor
