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ABSTRACT: Mismatch between the uptake and utilization of long-chain fatty acids in the myocardium leads to abnormally high intracellular fatty acid concentration, which ultimately induces myocardial dysfunction. Stearoyl-Coenzyme A desaturase-1 (SCD1) is a rate-limiting enzyme that converts saturated fatty acids (SFAs) to monounsaturated fatty acids. Previous studies have shown that SCD1-deficinent mice are protected from insulin resistance and diet-induced obesity; however, the role of SCD1 in the heart remains to be determined. We examined the expression of SCD1 in obese rat hearts induced by a sucrose-rich diet for 3 months. We also examined the effect of SCD1 on myocardial energy metabolism and apoptotic cell death in neonatal rat cardiac myocytes in the presence of SFAs. Here we showed that the expression of SCD1 increases 3.6-fold without measurable change in the expression of lipogenic genes in the heart of rats fed a high-sucrose diet. Forced SCD1 expression augmented palmitic acid-induced lipid accumulation, but attenuated excess fatty acid oxidation and restored reduced glucose oxidation. Of importance, SCD1 substantially inhibited SFA-induced caspase 3 activation, ceramide synthesis, diacylglycerol synthesis, apoptotic cell death, and mitochondrial reactive oxygen species (ROS) generation. Experiments using SCD1 siRNA confirmed these observations. Furthermore, we showed that exposure of cardiac myocytes to glucose and insulin induced SCD1 expression. Our results indicate that SCD1 is highly regulated by a metabolic syndrome component in the heart, and such induction of SCD1 serves to alleviate SFA-induced adverse fatty acid catabolism, and eventually to prevent SFAs-induced apoptosis.
PLoS ONE 01/2012; 7(3):e33283. · 4.09 Impact Factor
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Kana Aoyagi-Ikeda,
Toshitaka Maeno,
Hiroki Matsui, Manabu Ueno,
Kenichiro Hara,
Yasuhiro Aoki,
Fumiaki Aoki,
Takehisa Shimizu,
Hiroshi Doi,
Keiko Kawai-Kowase,
Tatsuya Iso,
Tatsuo Suga,
Masashi Arai,
Masahiko Kurabayashi
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ABSTRACT: Notch is an ancient cell-signaling system that regulates the specification of cell fate. This study examined the role of Notch in the epithelial-mesenchymal transition (EMT) and myofibroblast differentiation of cultured RLE-6TN cells (i.e., rat alveolar epithelial cells). The activation of Notch, either by ectopic expression of the Notch intracellular domain or by the co-culture of RLE-6TN cells with L-Jagged1 cells, induces the expression of smooth muscle α-actin (SMA) and other mesenchymal marker genes (collagen I and vimentin), and reduces the expression of epithelial marker genes (E-cadherin, occludin, and zonula occludens-1). The pharmacologic inhibition of the endogenous Notch signal significantly inhibited the transforming growth factor-β (TGF-β)-induced expression of SMA. Cell migratory capacity was increased by Notch. Luciferase assays revealed that the CC(A/T)(6)GG (CArG) box and the TGF-β control element (TCE) are required for Notch-induced SMA gene transcription. DNA microarray analysis revealed that members of the TGF-β family as well as Jagged1 were induced in RLE-6TN cells by Notch. Western blot analysis showed that Notch induced the phosphorylation of Smad3, and the TGF-β receptor type I/activin receptor-like kinase 5 (ALK5) kinase inhibitor SB431542 markedly reduced the Notch-induced expression of SMA. Enzyme-linked immunosorbent assays confirmed the production of TGF-β1 from RLE-6TN cells by Notch. Immunohistochemistry of a bleomycin-induced model of pulmonary fibrosis and lung specimens from patients with idiopathic interstitial pneumonias showed that Notch was strongly expressed in myofibroblasts, identified as SMA-positive cells. These data indicate that Notch induces myofibroblast differentiation through a TGF-β-Smad3 pathway that activates SMA gene transcription in a CArG-dependent and TCE-dependent manner in alveolar epithelial cells. Our data also imply that Notch induces the EMT phenotype, with increased migratory behavior in pulmonary fibrosis.
American Journal of Respiratory Cell and Molecular Biology 07/2011; 45(1):136-44. · 5.13 Impact Factor
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ABSTRACT: Hypoxia-inducible factor-1α (HIF-1α), a transcription factor that functions as a master regulator of oxygen homeostasis, has been implicated in fibrinogenesis. Here, we explore the role of HIF-1α in transforming growth factor-β (TGF-β) signaling by examining the effects of TGF-β(1) on the expression of plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of lung tissue from a mouse bleomycin (BLM)-induced pulmonary fibrosis model revealed that expression of HIF-1α and PAI-1 was predominantly induced in alveolar macrophages. Real-time RT-PCR and ELISA analysis showed that PAI-1 mRNA and activated PAI-1 protein level were strongly induced 7 days after BLM instillation. Stimulation of cultured mouse alveolar macrophages (MH-S cells) with TGF-β(1) induced PAI-1 production, which was associated with HIF-1α protein accumulation. This accumulation of HIF-1α protein was inhibited by SB431542 (type I TGF-β receptor/ALK receptor inhibitor) but not by PD98059 (MEK1 inhibitor) and SB203580 (p38 MAP kinase inhibitor). Expression of prolyl-hydroxylase domain (PHD)-2, which is essential for HIF-1α degradation, was inhibited by TGF-β(1), and this decrease was abolished by SB431542. TGF-β(1) induction of PAI-1 mRNA and its protein expression were significantly attenuated by HIF-1α silencing. Transcriptome analysis by cDNA microarray of MH-S cells after HIF-1α silencing uncovered several pro-fibrotic genes whose regulation by TGF-β(1) required HIF-1α, including platelet-derived growth factor-A. Taken together, these findings expand our concept of the role of HIF-1α in pulmonary fibrosis in mediating the effects of TGF-β(1) on the expression of the pro-fibrotic genes in activated alveolar macrophages.
AJP Lung Cellular and Molecular Physiology 01/2011; 300(5):L740-52. · 3.66 Impact Factor
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Kana Aoyagi-Ikeda,
Toshitaka Maeno,
Hiroki Matsui, Manabu Ueno,
Kenichiro Hara,
Yasuhiro Aoki,
Fumiaki Aoki,
Takehisa Shimizu,
Hiroshi Doi,
Keiko Kawai-Kowase,
Tatsuya Iso,
Tatsuo Suga,
Masashi Arai,
Masahiko Kurabayashi
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ABSTRACT: Notch is an ancient cell signaling system that regulates cell fate specification. This study examined the role of Notch in epithelial-mesenchymal transition (EMT) and myofibroblast differentiation of cultured RLE-6TN cells, rat alveolar epithelial cells. Activation of Notch, either by ectopic expression of Notch intracellular domain or by coculture of RLE-6TN cells with L-Jagged1 cells, induced the expression of the smooth muscle α-actin (SMA) and other mesenchymal marker genes (collagen I and vimentin) and reduced the expression of the epithelial marker genes (E-cadherin, occludin and zonula occludens-1). Pharmacological inhibition of endogenous Notch signal significantly inhibited transforming growth factor-β (TGF-β)-induced SMA expression. Cell migratory capacity was increased by Notch. Luciferase assays revealed that CArG box and TGF-β-control element (TCE) are required for Notch-induced SMA gene transcription. DNA microarray analysis revealed that members of TGF-β family as well as Jagged1 were induced in RLE-6TN cells by Notch. Western blot analysis showed that Notch induced phosphorylation of Smad3 and TGF-β receptor typeI/ALK5 kinase inhibitor SB431542 markedly reduced Notch-induced SMA expression. Enzyme-linked immunosorbent assays confirmed the production of TGF-β1 from RLE-6TN cells by Notch. Immunohistochemistry of bleomycin-induced pulmonary fibrosis model and lung specimens from idiopathic interstitial pneumonias patients showed that Notch was strongly expressed in myofibroblasts as identified as SMA-positive cells. These data indicate that Notch induces myofibroblast differentiation through TGF-ß/Smad3 pathway which activates SMA gene transcription in a CArG- and TCE-dependent manner in alveolar epithelial cells. Our data also imply that Notch induces EMT phenotype with an increased migratory behavior in pulmonary fibrosis.
American Journal of Respiratory Cell and Molecular Biology 09/2010; · 5.13 Impact Factor
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ABSTRACT: A 62-year-old man had had renal dysfunction and hepatosplenomegaly since 2000. In 2006, he complained of general fatigue and hemodialysis therapy was initiated because his renal function had deteriorated worse. In May 2007, he was admitted to our hospital because his general fatigue took a turn for the worse. He also had hypoxia. A chest radiograph showed no abnormal shadows. A chest computed tomography showed ground glass opacities in both lower lobes slightly. However, 67Ga-citrate scintigraph showed marked accumulation of 67Ga-citrate in the lungs, liver, spleen and kidneys. Transbronchial lung biopsy (TBLB) and bone marrow biopsy showed noncaseating epithelioid cell granulomas, and anti-PAB antibody positive cells were detected in epithelioid cell granulomas in the TBLB specimens. Therefore we diagnosed sarcoidosis. Although we could not perform renal or liver biopsy, we assumed that he had renal and liver sarcoidosis. After oral corticosteroid therapy, his symptoms and image findings improved. We report a rare case of sarcoidosis with hypoxia showing slight ground glass opacities
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 12/2008; 46(11):899-903.
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Yasuhiro Aoki,
Toshitaka Maeno,
Kana Aoyagi, Manabu Ueno,
Fumiaki Aoki,
Nozomi Aoki,
Junichi Nakagawa,
Yoshichika Sando,
Yuji Shimizu,
Tatsuo Suga,
Masashi Arai,
Masahiko Kurabayashi
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ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs. Objective: To investigate whether the PPARgamma ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis.
BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor- beta (TGF-beta) for 6 h.
PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day -7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-alpha production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-beta-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells.
These results suggest that activation of PPARgamma ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-alpha, procollagen I and CTGF expression. Beneficial effects of this PPARgamma ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARgamma as a molecular target in fibroproliferative lung diseases.
Respiration 11/2008; 77(3):311-9. · 2.26 Impact Factor
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ABSTRACT: A 54-year-old asymptomatic man was admitted to our hospital because his abnormal chest radiograph finding became worse. A chest radiograph and a chest computed tomography showed a mass in the right upper lobe and mediastinal lymphadenopathy. Thoracoscopic partial lung resection was performed. The specimens showed vasculitis and geographic basophilic necrosis palisading histiocytes and neutrophils. Wegener's granulomatosis was diagnosed. After resection, mediastinal lympahdenopathy was gradually improved in spite of no drug therapy. We report a rare case of Wegener's granulomatosis associated with lymphadenopathy.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 10/2008; 46(9):732-6.
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ABSTRACT: A 54-year old man was admitted to our hospital because of high fever, productive cough and purpura in both legs in June 2005. Urinalysis showed microscopic hematuria and proteinuria. Chest radiograph showed consolidation of right upper field. Because acid-fast bacilli and polymerase chain reaction test for Mycobacterium tuberculosis were positive in bronchial lavage fluid, we made a diagnosis of pulmonary tuberculosis, and prescribed antituberculosis therapy with isoniazid, rifampicin, ethambutol and pyrazinamide. In addition, anaphylactoid purpura was diagnosed by skin biopsy. In July 2005, renal function was deteriorated and nephrosis appeared. We treated with corticosteroid in addition to antituberculosis therapy. His symptoms and renal dysfunction improved. We report a rare case of an anaphylactoid purpura following occurence of pulmonary tuberculosis.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 09/2008; 46(8):645-9.
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ABSTRACT: A 54-year old man was admitted with general fatigue, muscle weakness and dyspnea on effort. Medical examinations led to a diagnosis of small cell lung carcinoma (SCLC) with Lambert-Eaton myasthenic syndrome (LEMS). Marked improvement of SCLC and symptoms of LEMS were recognized twice during chemoradiotherapy. On his third admission, he showed muscle weakness, dysaethesia, and neurodysfunction of the bladder and rectum. We initially considered these symptoms to be due to spinal metastasis because MRI findings showed multiple spinal metastases. However, electoromyogram and nerve conduction study demonstrated that his muscle weakness resulted from LEMS though dysethesia and neurodysfunction of bladder and rectum were caused by spinal metastasis. We believe that it is important to perform electomyogram and nerve conduction studies, not only radiographic findings, to detect the "hidden" symptoms of LEMS.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 04/2008; 46(3):226-31.
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Zen Isobe,
Tatsuo Suga,
Shigeto Hamaguchi,
Shouzaburou Yamaguchi,
Kenichirou Hara,
Fumiaki Aoki,
Nozomi Aoki,
Kana Aoyagi, Manabu Ueno,
Toshitaka Maeno,
Masahiko Kurabayashi
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ABSTRACT: A 69-year-old woman had been found to have idiopathic interstitial pneumonia (fibrotic NSIP) in 1997. Proximal muscle weakness appeared in April 2005. Chest CT revealed hilar and mediastinal lymphadenopathy. Polymyositis and Sjögren's syndrome were subsequently diagnosed. We assumed that the interstitial pneumonia had preceded polymyositis and Sjögren's syndrome. A muscle biopsy and transbronchial needle aspiration biopsy demonstrated noncaseating epithelioid cell granulomas. A diagnosis of sarcoidosis complicated with polymyositis and Sjögren's syndrome was made from these findings. Moreover, her HLA genotype contained DR8. HLA-DR8 is considered to be associated with polymyositis, Sjögren's syndrome, and sarcoidosis in Japanese patients. This case suggests the possibility that there are common immunological and genetical pathogenetic mechanisms in autoimmune diseases and sarcoidosis.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 03/2008; 46(2):96-100.
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Zen Isobe,
Tatsuo Suga,
Shigeto Hamaguchi,
Shozaburo Yamaguchi,
Kenichirou Hara,
Fumiaki Aoki,
Nozomi Aoki,
Kana Aoyagi, Manabu Ueno,
Toshitaka Maeno,
Masahiko Kurabayashi
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ABSTRACT: A 36-year-old Philippine woman had had fever and general fatigue from September, 2006 (11th week of pregnancy). She was admitted with high fever, general fatigue and dyspnea on October 16, 2006 (13th week of pregnancy). A chest radiograph on admission showed bilateral miliary shadows and ground glass shadows. She already had severe hypoxia on admission. As acid-fast bacilli were positive in urine (Gaffky 8) and sputum (Gaffky 1), we diagnosed as miliary tuberculosis and pulmonary tuberculosis complicated with acute respiratory distress syndrome (ARDS). We treated her with antituberculosis chemotherapy, corticosteroid, sivelestat sodium hydrate, direct hemoperfusion using a polymyxin B immobilized column, and mechanical ventilation, but she died due to respiratory failure. We emphasize that in this case pregnancy has the risk of to causing disease progression of miliary tuberculosis and we should treat immediately and intensively for miliary tuberculosis complicated with ARDS.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 12/2007; 45(11):874-8.
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ABSTRACT: A 58-year-old woman had a productive cough but not from bronchial asthma. A chest radiograph revealed infiltrative shadows in right middlelung field on September, 2004. Aspergillus fumigatus was detected in a sputum culture. She was treated with oral itraconazole. After the treatment, infiltrative shadows on her chest radiograph disappeared. On October 2005, her peripheral blood showed eosinophilla, a high serum level of total immunoglobulin E (IgE), and a chest radiograph revealed new infiltrative shadows in both lung fields. A chest computed tomography revealed multiple nodular shadows and central bronchiectasis. We detected a mucoid plug which showed a large number of eosinophils pathologically by bronchoscopy. Aspergillus niger was detected in a bronchial lavage fluid. We therefore made a diagnosis of allergic bronchopulmonary aspergillosis (ABPA). The decreases of peripheral blood eosinophils and a serum IgE level were recognized and multiple nodular shadows disappeared by reinstitution of itraconazole. However, a chest computed tomography revealed new infiltrative shadows. Therefore, we treated her with the concomitant administration of oral itraconazole and inhaled corticosteroid. All laboratory data and image findings were improved. It is critical to consider the both aspects of allergy and infection in the treatment for ABPA.
Arerugī = [Allergy] 12/2007; 56(11):1390-6.
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Zen Isobe,
Tatsuo Suga,
Shigeto Hamaguchi,
Shouzaburou Yamaguchi,
Kenichirou Hara,
Fumiaki Aoki,
Nozomi Aoki,
Kana Aoyagi, Manabu Ueno,
Toshitaka Maeno,
Kenji Kasiwabara,
Masahiko Kurabayashi,
Yoshinori Kawabata
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ABSTRACT: A 66-year-old man was admitted because of general fatigue. A chest computed tomography showed bilateral alveolar consolidation and ground glass opacities. Although we treated him with broad-spectrum antibiotics, his symptoms and chest image findings did not improve. Thoracoscopic lung biopsy (rS2, S9) was performed. The specimens showed obstructive type intraluminar organization and interstitial inflammatory thickening. Membranous organization was seen in a limited area. The etiology of the illness could not be identified. We diagnosed acute interstitial pneumonia (AIP) because the specimens showed diffuse alveolar damage pattern (DAD/P) and because of unknown etiology. The symptoms and chest image findings were improved on treatment with corticosteroid and cyclophosphamide. However, he was readmitted because of dyspnea 6 months later after the thoracoscopic lung biopsy. Chest computed tomography showed bilateral diffuse ground glass opacities and reticular opacities in both lower lobes. We employed mechanical ventilation, antibiotics, sivelestat sodium hydrate and steroid pulse therapy, but he died without any response to treatment. The findings of autopsy revealed DAD/P accompanied by a new lesion mainly composed of membranous organization and hyaline membrane. We believe this case is valuable when considering the variety of responses to treatment of AIP and prognosis.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 11/2007; 45(10):772-8.
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Zen Isobe,
Tatsuo Suga,
Shigeto Hamaguchi,
Shouzaburou Yamaguchi,
Kenichirou Hara,
Fumiaki Aoki,
Nozomi Aoki,
Kana Aoyagi, Manabu Ueno,
Toshitaka Maeno,
Masahiko Kurabayashi
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ABSTRACT: A 68 year-old woman was admitted with fever, productive cough and sore throat. A chest radiograph and a chest computed tomography showed multiple nodules in both lungs. Thoracoscopic lung biopsy was performed. The specimens showed vasculitis and geographic basophilic necrosis with palisading histiocytes, giant cells, and neutrophils. Wegener's granulomatosis was diagnosed. On the 5th hospital day, the serum sodium level was 128 mEq/l. Since secretion of antidiuretic hormone had continued despite a low plasma osmolarity, we diagnosed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and initiated oral prednisolone and cyclophosphamide. As a result, the symptoms and image findings were improved, and serum sodium level became normal. This case was considered to be SIADH secondary to Wegener's granulomatosis.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 10/2007; 45(9):679-84.
