RESUMEN
BACKGROUND: Postoperative pulmonary complications (PPC) in patients with pulmonary diseases remain to be resolved clinical issue. However, most evidence regarding PPC has been established more than 10 years ago. Therefore, it is necessary to evaluate perioperative management using new inhalant drugs in patients with obstructive pulmonary diseases. METHODS: April 2014 through March 2015, 346 adult patients with pulmonary diseases (257 asthma, 89 chronic obstructive pulmonary disease (COPD)) underwent non-pulmonary surgery except cataract surgery in our university hospital. To analyze the risk factors for PPC, we retrospectively evaluated physiological backgrounds, surgical factors and perioperative specific treatment for asthma and COPD. RESULTS: Finally, 29 patients with pulmonary diseases (22 asthma, 7 COPD) had PPC. In patients with asthma, smoking index (≥ 20 pack-years), peripheral blood eosinophil count (≥ 200/mm3) and severity (Global INitiative for Asthma(GINA) STEP ≥ 3) were significantly associated with PPC in the multivariate logistic regression analysis [odds ratio (95% confidence interval) = 5.4(1.4-20.8), 0.31 (0.11-0.84) and 3.2 (1.04-9.9), respectively]. In patients with COPD, age, introducing treatment for COPD, upper abdominal surgery and operation time (≥ 5 h) were significantly associated with PPC [1.18 (1.00-1.40), 0.09 (0.01-0.81), 21.2 (1.3-349) and 9.5 (1.2-77.4), respectively]. CONCLUSIONS: History of smoking or severe asthma is a risk factor of PPC in patients with asthma, and age, upper abdominal surgery, or long operation time is a risk factor of PPC in patients with COPD. Adequate inhaled corticosteroids treatment in patients with eosinophilic asthma and introducing treatment for COPD in patients with COPD could reduce PPCs.
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Asma/epidemiología , Neutrófilos , Complicaciones Posoperatorias/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Abdomen/cirugía , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Asma/sangre , Asma/fisiopatología , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Tempo Operativo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Fumar/epidemiología , Adulto JovenRESUMEN
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 ß-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.
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Autofagia/fisiología , Bronquios/patología , Senescencia Celular/fisiología , Células Epiteliales/patología , Factor I del Crecimiento Similar a la Insulina/fisiología , Enfermedad Pulmonar Obstructiva Crónica/patología , Sirtuinas/fisiología , Humo/efectos adversos , Acetilación , Proteína 5 Relacionada con la Autofagia , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Células Epiteliales/metabolismo , Volumen Espiratorio Forzado , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Asociadas a Microtúbulos/fisiología , Mutación , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-akt/fisiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Transducción de Señal/fisiología , Sirtuinas/antagonistas & inhibidores , Sirtuinas/genética , Serina-Treonina Quinasas TOR/fisiología , Nicotiana , Capacidad VitalRESUMEN
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.
RESUMEN
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 ß-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.
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Bronquios/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Forma BB de la Creatina-Quinasa/metabolismo , Células Epiteliales/efectos de los fármacos , Humo/efectos adversos , Fumar/efectos adversos , Bronquios/enzimología , Bronquios/inmunología , Bronquios/patología , Células Cultivadas , Forma BB de la Creatina-Quinasa/antagonistas & inhibidores , Forma BB de la Creatina-Quinasa/genética , Ciclina B1/metabolismo , Regulación hacia Abajo , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/enzimología , Células Epiteliales/inmunología , Células Epiteliales/patología , Humanos , Inmunohistoquímica , Interleucina-8/metabolismo , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Carbonilación Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Ubiquitinación , beta-Galactosidasa/metabolismoRESUMEN
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.
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Apoptosis/inmunología , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Insulina/fisiología , Sistema de Señalización de MAP Quinasas/inmunología , Fosfatidilinositol 3-Quinasa/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Mucosa Respiratoria/inmunología , Receptor Toll-Like 3/antagonistas & inhibidores , Bronquios/enzimología , Bronquios/inmunología , Bronquios/patología , Células Cultivadas , Humanos , Mucosa Respiratoria/enzimología , Mucosa Respiratoria/patología , Receptor Toll-Like 3/fisiologíaRESUMEN
Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated ß-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-ß-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1ß expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-ß induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-ß also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-ß-induced senescence via proteasomal degradation of p21. TGF-ß-induced senescent HBEC secreted increased amounts of IL-1ß, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.
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Bronquios/patología , Senescencia Celular/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibrosis Pulmonar Idiopática/patología , Sirtuinas/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Diferenciación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Células Epiteliales/efectos de los fármacos , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Interleucina-1beta/metabolismo , Miofibroblastos/citología , Miofibroblastos/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , beta-Galactosidasa/metabolismoRESUMEN
A 63-year-old man was admitted to Jikei University Hospital, with anasarca, and dyspnea in May, 2004. Echocardiograms and CT scans showed massive pericardial effusion, nodules on the pericardium and a tumor in the lower lobe of the left lung. Pathological examination of the punctured pericardial effusions yielded a diagnosis of pericardial malignant mesothelioma. However, no pathogen or malignant cells were identified from multiple biopsy specimens of the lung tumor, which were obtained by brochoscopic techniques. Since he worked as a fisherman in a diesel-powered fishing boat, he was possibly exposed to asbestos. On autopsy, the lung tumor was diagnosed as a primary lung adenocaricinoma. Exposure to asbestos is an important risk factor for both mesothelioma and lung cancer. However, pericardial malignant mesothelioma in itself is rare among mesothelioma. This is only the second report of malignant mesothelioma with primary lung adenocarcinoma, to date.
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Adenocarcinoma/patología , Neoplasias Cardíacas/patología , Neoplasias Pulmonares/patología , Mesotelioma/patología , Neoplasias Primarias Múltiples/patología , Pericardio , Asbestosis/patología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A 64-year-old woman presented skin lesions on her face, upper extremities and finger erythema (heliotropism and Gottron's sign). She had weakness in her lower extremities. She was given a diagnosis of dermatomyositis (DM), because the serum examination showed that a myositis-specific antibody was positive whereas Jo-1 antibody was negative. The findings of chest X-ray and computed tomography showed that she had limited small cell lung cancer, but no interstitial pneumonia. She was treated with standard chemotherapy consisting of cisplatin and etoposide with accelerated hyperfractionation radiotherapy. She showed partial response to the treatment, whereas the skin lesions and muscle weakness deteriorated accompanied with bone marrow suppression due to chemotherapy. Skin and muscle biopsy were performed and pathological findings showed typical perivasculitis infiltrated with lymphocytes in muscle and skin. With the recovery of bone marrow suppression and partial response due to chemotherapy, the skin lesions improved and creatine kinase became normalized. She was given a diagnosis of paraneoplastic DM. Since severe leukocytopenia paralleled the deterioration of DM, the decrease of peripheral white blood cell counts, especially regulatory T cell counts, may be associated with DM activity.