Noriki Kamiya

Insufficient autophagy in idiopathic pulmonary fibrosis

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.

Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence.

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.

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated β-galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial-specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito-TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development.

Morgagni hernia diagnosed by MRI

We herein present a patient with Morgagni hernia which was diagnosed by magnetic resonance imaging (MRI). The patient had a progressively enlarging mass in the right cardiophrenic angle on chest roentgenogram. On computed tomography (CT) scans, the mass was revealed to have fat density and therefore was suspected to be either a lipoma or liposarcoma. MRI clearly demonstrated that the mass shadow was composed of omental fat herniating into the right thorax through the diaphragmatic hiatus. MRI is thus considered to be a useful noninvasive modality for the evaluation of lower anterior mediastinal masses demonstrating fat density on CT.

Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD

BackgroundMarked 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.MethodsImmunohistochemical 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.ResultsThe 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.ConclusionsThese results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.

Anomalous Systemic Arterial Supply to the Basal Segments of the Lung: Feasible Thoracoscopic Surgery

BACKGROUND Anomalous systemic arterial supply to the basal segments of the lung is a rare anomaly. This study aimed to evaluate the outcomes of thoracoscopic surgery for this anomaly. METHODS We reviewed patients who underwent thoracoscopic surgery for anomalous systemic arterial supply to the basal segments of the lung between October 2007 and September 2012 at our institution. RESULTS Four patients (mean age 37.5 years; range, 22 to 54) underwent thoracoscopic surgery for anomalous systemic arterial supply to the basal segments of the lung. The mean diameter of the anomalous arteries was 14 mm (range, 10 to 16 mm). Two patients underwent thoracoscopic segmentectomy, 1 of whom had a complicated anomaly that necessitated conversion to thoracotomy. The other 2 patients underwent thoracoscopic lower lobectomy of the left lung. One of them had an aneurysm in the anomalous artery; therefore, endovascular devices were kept on standby in case massive hemorrhage occurred. The anomalous arteries were divided uneventfully using a vascular stapler in all patients. No patient had severe postoperative complications. CONCLUSIONS Thoracoscopic surgery for anomalous systemic arterial supply to the basal segments of the lung is feasible, safe, and minimally invasive, with confirmed effectiveness in typical cases.

Oncological outcomes of thoracoscopic thymectomy for the treatment of stages I–III thymomas

OBJECTIVES Thoracoscopic thymectomy has gradually replaced conventional sternotomy for resection of thymoma; however, a thoracoscopic approach for thymoma remains controversial. We evaluated the oncological outcomes of thoracoscopic thymectomy for the treatment of stages I-III thymomas. METHODS Sixty-two patients who underwent thoracoscopic thymectomy for the treatment of thymoma were retrospectively reviewed between July 2005 and September 2011 at Jikei University Hospital. Surgical outcomes and pathological results between stages I+II and stage III were compared. RESULTS Twenty-nine patients had Masaoka stage I, 28 had stage II and 5 had stage III. Three stage III patients needed conversions to open surgery. Masaoka stage III comprised pathological type B3 in 3 patients and thymic carcinoma in 2. For all patients, the 5-year overall survival rate was 100%. Three recurrences, diagnosed as thymic carcinoma, were observed in the Masaoka stage II or III patients. The 5-year disease-free survival rate was 94.2% for all patients, 100% for Masaoka stage I, 96.1% for stage II and 37.5% (55 months) for stage III (P=0.002). The 5-year disease-free survival rate was 100% for the World Health Organization classification types A, AB and B1-3 and 0% for thymic carcinoma (P<0.0001). Significant differences were found in the 5-year disease-free survival stratified by the Masaoka stage or WHO classification, but not by surgical procedures. CONCLUSIONS Thoracoscopic thymectomy for Masaoka stages I and II thymomas presented acceptable oncological outcomes. Further investigation in a large series with longer follow-up is required. Masaoka stage III thymoma requires careful consideration of the approaches, including median sternotomy.

Huge localized mesothelioma of the diaphragm in a 17-year-old Female — a case report with calculated tumor volume doubling time —

An operative case of localized mesothelioma of the pleura developed in a 17-year-old female was reported. She was admitted to our hospital complaining of right chest pain. A chest X-ray film showed a huge mass in the right lower field of the lung. After the embolization of the right inferior phrenic artery, which was the main feeder to the tumor, it was then successfully resected combined with the right diaphragm and the right lower lobe of the lung. Histologically, the tumor was diagnosed as benign localized mesothelioma (solitary fibrous tumor of the pleura). Further histological and immunohistochemical study revealed that it had developed from the connective tissue under the parietal mesothelium of the diaphragm. As chest roentgenograms had been undertaken during past two years, the tumor volume doubling time was calculated at 153 days. Despite the short tumor volume doubling time as like primary lung cancer, she is alive without recurrence 5 years after the operation.

Thoracoscopic resection of a mediastinal venous hemangioma: Report of a case

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.

Thoracoscopic resection for a pulmonary nodule with the infiltrate of IgG4-positive plasma cells.

This report describes a rare case of IgG4‐related lung disease that was difficult to distinguish from lung cancer. CT revealed a well‐demarcated round tumor in S10 of the right lung of a 56‐year‐old man suspected of having lung cancer. PET revealed high fluorodeoxyglucose uptake with a maximum standardized uptake value of 14.0. Because primary lung cancer was strongly suspected, lower lobectomy was performed via the thoracoscopic approach without mini‐thoracotomy. Histopathology showed lymphoplasmacytic infiltration. Immunostaining revealed numerous IgG4‐positive plasma cells diffusely infiltrating the tumor. Serum IgG4 levels increased, thereby confirming the diagnosis of IgG4‐related lung disease.