Jun Hirano

The Jikei University School of Medicine, Tokyo, Tokyo-to, Japan

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Publications (13)32.81 Total impact

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    ABSTRACT: Cigarette smoke (CS)-induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.
    The Journal of Immunology 12/2013; · 5.52 Impact Factor
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    ABSTRACT: BACKGROUND: Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure. METHODS: Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM. RESULTS: The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure. CONCLUSIONS: These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.
    Respiratory research 03/2013; · 3.64 Impact Factor
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    ABSTRACT: Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure. Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM. The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure. These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.
    Respiratory research 01/2013; 14:30. · 3.64 Impact Factor
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    ABSTRACT: Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type specific manner and is a promising clue for understanding the pathogenesis of IPF.
    AJP Lung Cellular and Molecular Physiology 10/2012; · 3.52 Impact Factor
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    ABSTRACT: Tobacco smoke-induced accelerated cell senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cell senescence is accompanied by the accumulation of damaged cellular components suggesting that in COPD, inhibition of autophagy may contribute to cell senescence. Here we look at whether autophagy contributes to cigarette smoke extract (CSE) - induced cell senescence of primary human bronchial epithelial cells (HBEC), and further evaluate p62 and ubiquitinated protein levels in lung homogenates from COPD patients. We demonstrate that CSE transiently induces activation of autophagy in HBEC, followed by accelerated cell senescence and concomitant accumulation of p62 and ubiquitinated proteins. Autophagy inhibition further enhanced accumulations of p62 and ubiquitinated proteins, resulting in increased senescence and senescence-associated secretory phenotype (SASP) with interleukin (IL)-8 secretion. Conversely, autophagy activation by Torin1, a mammalian target of rapamycin (mTOR inhibitor), suppressed accumulations of p62 and ubiquitinated proteins and inhibits cell senescence. Despite increased baseline activity, autophagy induction in response to CSE was significantly decreased in HBEC from COPD patients. Increased accumulations of p62 and ubiquitinated proteins were detected in lung homogenates from COPD patients. Insufficient autophagic clearance of damaged proteins, including ubiquitinated proteins, is involved in accelerated cell senescence in COPD, suggesting a novel protective role for autophagy in the tobacco smoke-induced senescence-associated lung disease, COPD.
    Oncoimmunology. 08/2012; 1(5):630-641.
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    ABSTRACT: Cigarette smoke induces damage to proteins and organelles by oxidative stress, resulting in accelerated epithelial cell senescence in the lung, which is implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Although the detailed molecular mechanisms are not fully understood, cellular energy status is one of the most crucial determinants for cell senescence. Creatine kinase (CK) is a constitutive enzyme, playing regulatory roles in energy homeostasis of cells. Among two isozymes, brain-type CK (CKB) is the predominant CK in lung tissue. In this study, we investigated the role of CKB in cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBECs). Primary HBECs and Beas2B cells were used. Protein carbonylation was evaluated as a marker of oxidative protein damage. Cellular senescence was evaluated by senescence-associated β-galactosidase staining. CKB inhibition was examined by small interfering RNA and cyclocreatine. Secretion of IL-8, a hallmark of senescence-associated secretary phenotype, was measured by ELISA. CKB expression levels were reduced in HBECs from patients with COPD compared with that of HBECs from nonsmokers. CSE induced carbonylation of CKB and subsequently decreased CKB protein levels, which was reversed by a proteasome inhibitor. CKB inhibition alone induced cell senescence, and further enhanced CSE-induced cell senescence and IL-8 secretion. CSE-induced oxidation of CKB is a trigger for proteasomal degradation. Concomitant loss of enzymatic activity regulating energy homeostasis may lead to the acceleration of bronchial epithelial cell senescence, which is implicated in the pathogenesis of COPD.
    American Journal of Respiratory Cell and Molecular Biology 03/2012; 46(3):306-12. · 4.15 Impact Factor
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    ABSTRACT: Mediastinal hemangioma is a rare tumor, accounting for 0.5% or fewer of all mediastinal tumors in most reports. We herein report a case of thoracoscopic resection of venous hemangioma in the middle mediastinum. A 48-year-old man was referred to our hospital for dysphagia. A chest computed tomography scan showed the mass to have a smooth surface and heterogeneous contents. Magnetic resonance imaging demonstrated the morphology of the vascular tumor to be a hyperintense mass on a T2-weighted image. Using thoracoscopic surgery, the tumor was completely extirpated and confirmed histologically to be a venous hemangioma. In this case, thoracoscopic surgery provided a satisfactory view and facilitated correct handling for the mediastinal venous hemangioma.
    Surgery Today 10/2011; 41(10):1455-7. · 0.96 Impact Factor
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    ABSTRACT: TLR3, one of the TLRs involved in the recognition of infectious pathogens for innate and adaptive immunity, primarily recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of toxicity, suggesting a pivotal participation of TLR3 in viral infection, as well as in lung diseases where apoptosis plays a critical role, such as asthma and chronic obstructive pulmonary disease. In addition to metabolic control, insulin signaling was postulated to be protective by inhibiting apoptosis. Therefore, we explored the role of insulin signaling in protecting against TLR3-mediated apoptosis of human bronchial epithelial cells. Significant TLR3-mediated apoptosis was induced by polyinosinic-polycytidylic acid, a dsRNA analog, via caspase-8-dependent mechanisms. However, insulin efficiently inhibited TLR3/polyinosinic-polycytidylic acid-induced human bronchial epithelial cell apoptosis via PI3K/Akt and ERK pathways, at least in part, via upregulation of cellular FLIPs and through protein synthesis-independent mechanisms. These results indicate the significance of TLR3-mediated dsRNA-induced apoptosis in the pathogenesis of apoptosis-driven lung disease and provide evidence for a novel protective role of insulin.
    The Journal of Immunology 07/2011; 187(1):510-9. · 5.52 Impact Factor
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    ABSTRACT: We describe herein a case of a 68-year-old woman with primary lung cancer who had undergone induction chemoradiotherapy and then a right pneumonectomy for non-small cell cancer (adenocarcinoma). Twenty-one months later, the cancer had metastasized to the brain, which was treated with 2-knife radiosurgery. She had been well for up to 32 months; however, the chest radiography and chest computed tomography (CT) demonstrated a nodule in the left upper lobe of the lung that was gradually growing. We preformed a partial resection of the left upper lobe by video-assisted thoracic surgery (VATS) under percutaneous cardiopulmonary support (PCPS), considering the oxygenation requirement of the patient. PCPS was applied via venoarterial (V-A) bypass, and the hemodynamic status of the patient was mostly stable. The postoperative course was uneventful, and the patient has no evidence of metastatic lung cancer, 10 months postoperatively, indicating that the minimally invasive VATS under PCPS was successful and safe. Although few reports have been described and some key questions remain unanswered, the method appears to be promising.
    Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia. 02/2011; 17(1):45-7.
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    ABSTRACT: A serious complication following primary lung cancer surgery on patients with interstitial pneumonia (IP) is the postoperative acute exacerbation of IP. Because few studies have examined the feasibility of using video-assisted thoracic surgery (VATS) on these patients, we reviewed our experience with this technique. We examined 78 patients; 11 had IP (IP group) and 67 did not (non-IP group). Patients in the IP group were older than those in the non-IP group (p = 0.097), and they had a significantly higher incidence of squamous cell carcinoma than patients in the non-IP group (p = 0.002). Dominating the IP group, though not statistically significant, were males, the intention to undergo VATS, and limited surgery. VATS was performed on 10 lesions in the IP group and on 45 in the non-IP group. No surgery-related exacerbation of preoperative IP or development of postoperative IP was found in either group. VATS is the preferred surgical choice for lung cancer patients with IP.
    Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia. 08/2010; 16(4):236-41.
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    ABSTRACT: Introduction: The thoracoscopic approach is becoming the standard for intrathoracic neurogenic tumors, though certain technical issues still need to be resolved. The purpose of this study is to evaluate the feasibility of thoracoscopic surgery for intrathoracic neurogenic tumors.Methods: We evaluated short-term outcomes of 14 consecutive patients who underwent resection of intrathoracic neurogenic tumors between July 2005 and June 2009. Among them, three patients had tumors located at the thoracic apex, and one had a tumor with an intraspinal extension (dumbbell-type tumor).Results: A complete thoracoscopic resection was achieved in all patients with no postoperative mortality. The dumbbell-type tumor was resected with a combined neurosurgical–thoracoscopic approach. The postoperative course was uneventful in all patients.Conclusion: Our thoracoscopic approach was able to obtain satisfactory visualization of the field and enabled safe surgery for intrathoracic neurogenic tumors. This approach is minimally invasive and is indicated even for tumors located at the thoracic apex or those with intraspinal extensions.
    Asian Journal of Endoscopic Surgery 01/2010; 3(3):122-126.
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    ABSTRACT: The purpose of this study was to determine the feasibility of thoracoscopic thymectomy for the treatment of Masaoka stage I and II thymoma. We evaluated the short-term outcomes of 40 patients undergoing surgery for Masaoka stage I and II thymomas without myasthenia gravis between July 2000 and July 2008. Of these, 22 patients underwent complete thymoma resection using unilateral thoracoscopic subtotal thymectomy (UTST group), and 18 patients underwent trans-sternal thymectomy (TST group). Intra-operative blood loss amounts did not differ significantly between the UTST and TST groups (100.6 ml and 208.1 ml, respectively, p=0.0513). The duration of the postoperative hospital stay was significantly shortened in the UTST group (4.6 days vs 11.2 days, p<0.0001). No patient in the UTST group underwent conversion to open surgery. No severe surgical complications, such as bleeding due to injury to the left brachiocephalic vein, and no postoperative complications, were detected in this series. These preliminary results suggest that thoracoscopic thymectomy for Masaoka stage I and II thymoma is technically feasible and safe, and it is less invasive for the patient. Nevertheless, this procedure requires further investigation in a large series with a longer follow-up.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 11/2009; 37(4):824-6. · 2.40 Impact Factor
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    ABSTRACT: A 22-year-old man was referred for hemoptysis and general fatigue after exercise. Arteriography demonstrated an anomalous artery arising from the descending aorta supplying the lingular and all of the basal segments of the left lung. The feeding areas of the pulmonary and anomalous arteries were mutually exclusive. He underwent division of the anomalous artery and combined resection of the diseased segments. The upper division of the upper lobe and the superior segment of the lower lobe were spared. His symptoms were greatly improved postoperatively. The preoperative anatomic evaluation of anomalous vessels is crucial in surgical management.
    The Annals of thoracic surgery 10/2009; 88(4):1358-60. · 3.45 Impact Factor