RESUMEN
Smoking cessation is the cornerstone of COPD management, but difficult to achieve in clinical practice. The effect of comorbidities on smoking cessation and risk factors for mortality were studied in a cohort of 739 COPD patients recruited in two Finnish University Hospitals. The diagnosis of COPD was done for the first time on average 5.5 years prior to the enrollment. Data from the medical records and followup questionnaires (years 0, 1, 2, and 4) have been analyzed. The patients' lung function varied greatly; mean FEV(1) 58% of predicted. A total of 60.2% of men and 55.6% of women had been able to quit smoking. Alcohol abuse (OR 2.1, 95% CI 1.4-3.3) and psychiatric conditions (OR 1.8, 95% CI 1.2-2.7) were strongly related to low success rates of quitting. Among current smokers high nicotine dependency was again explained by alcohol abuse and psychiatric conditions. Non-quitters were younger than quitters, but their mortality rates remained significantly higher even when the model was adjusted for impairment of lung functions and comorbidities. In conclusion, co-existing addiction and psychiatric diseases significantly decreased the success rates in smoking cessation and increased mortality among the patients.
RESUMEN
Serum surfactant protein (SP)-A has been postulated to associate with pulmonary fibrosis, but its role in cigarette smoking-related lung diseases is undefined. SP-A levels in plasma and induced sputum in nonsmokers, smokers with respiratory symptoms (cough and/or phlegm) and symptom-free smokers were assessed using a validated EIA method. A total of 474 current smokers without any diseases or medications were enrolled and followed for 2 yrs with 111 of them succeeding in stopping. Plasma SP-A level was detectable in all subjects and elevated in smokers independently of the symptoms compared to nonsmokers (p = 0.001). After 2 yrs of follow-up, the SP-A level was higher in those who continued smoking compared to the quitters (p<0.001). Plasma SP-A levels were associated with age, smoking history and lung function. Sputum (n = 109) SP-A was nondetectable in most nonsmokers, whereas smoking and symptoms increased sputum SP-A highly significantly (p = 0.001). In conclusion, SP-A may be involved in pathogenesis of cigarette smoking-related lung diseases. Further studies are needed to elucidate the role of SP-A in chronic obstructive pulmonary disease.
Asunto(s)
Proteína A Asociada a Surfactante Pulmonar/sangre , Fumar/sangre , Esputo/química , Factores de Edad , Anciano , Tos/inducido químicamente , Tos/fisiopatología , Femenino , Humanos , Estudios Longitudinales , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Cese del Hábito de FumarRESUMEN
BACKGROUND: Diisocyanate-induced asthma (DIA) is known to be associated with poor prognosis. We wished to clarify if matrix metalloproteinases (MMP)-7, -8 or -9 or tissue inhibitor of matrix metalloproteinases (TIMP-1) are associated with the functional or inflammatory outcome in DIA patients. METHODS: This is a longitudinal study where 17 patients with DIA diagnosed by a specific challenge test to diisocyanates were monitored. Exposure to diisocyanates was terminated seven (mean) months before the challenge test. The studies included spirometry, histamine challenge test and bronchoscopy. MMP-7, MMP-8, TIMP-1 [Enzyme-linked immunosorbent assay (ELISA)- and immunofluorometric assay-methods], MMP-9 (ELISA and zymography), interferon-gamma, tumour necrosis factor-alpha, interleukin-6, -8, -15, -17, CXCL-5/ENA-78, monocyte chemoattractant protein-1 and macrophage inhibitory factor (MIF) (ELISA) were assayed from bronchoalveolar lavage (BAL) fluid. Inhaled steroid therapy was initiated after the examinations, which were repeated at 6 months and at 3 years during the treatment. The results were compared with those of 15 healthy controls. RESULTS: Inhaled steroid medication increased BAL levels of MMP-9 and MMP-9/TIMP-1 and decreased MMP-7 and MMP-7/TIMP-1. The increase in MMP-9 levels was associated with a decline in the TH-2 type inflammation. CONCLUSIONS: Our data suggest that reduced TH-2 type inflammation in DIA after inhaled steroid medication is reflected as elevated MMP-9 and MMP-9/TIMP-1 levels in BAL. MIF may be the inducer of MMP-9. This might point to some protective role for MMP-9 in DIA.
Asunto(s)
Asma/etiología , Asma/metabolismo , Corticoesteroides/uso terapéutico , Adulto , Antiasmáticos/uso terapéutico , Asma/diagnóstico , Asma/tratamiento farmacológico , Biomarcadores , Líquido del Lavado Bronquioalveolar , Estudios de Casos y Controles , Citocinas/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Metaloproteinasa 7 de la Matriz , Metaloproteinasa 8 de la Matriz , Metaloproteinasa 9 de la Matriz , Persona de Mediana Edad , Pruebas de Función Respiratoria , Factores de Riesgo , Células Th2/inmunología , Células Th2/metabolismo , Inhibidor Tisular de Metaloproteinasa-1RESUMEN
This study aims to compare diagnostic and clinical outcomes of Chronic Obstructive Pulmonary Disease (COPD) from the gender perspective using retrospective health care data and patient reported outcomes in a real-world setting. An electronic database was constructed from complete medical records of 844 COPD patients who were recruited in Helsinki and Turku University Central Hospitals during the years 2005-07. The patients were identified from the hospital discharge registries by ICD10 code J44.8 in the age group of 18-75 years of age. The medical history was obtained from all healthcare providers who had treated these patients during the previous 5-10 years; the study intends to continue their follow-up annually for the next 10 years. Thirty-six percent (N = 266) of the participants were women. The COPD diagnosis had been made at the same age for both genders. Women, however, reported significantly less pack-years than men. Compared to the men, the women displayed less advanced airway obstruction, but more severe gas transfer impairment. Parenchymal damage when evaluated by diffusion capacity correlated significantly stronger with FEV(1) (% of predicted) in women than men. The BMI index of the women was lower than that of the men. Cardiovascular diseases, diabetes and alcoholism were significantly more common in men, but women suffered more psychiatric conditions, especially depression. This cohort showed several significant gender dependent differences in the clinical presentation that need to taken under consideration in the assessment of COPD progression and the disease management.
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Fumar/epidemiología , Adolescente , Adulto , Anciano , Distribución de Chi-Cuadrado , Comorbilidad , Progresión de la Enfermedad , Femenino , Finlandia/epidemiología , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Pruebas de Función Respiratoria , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Estadísticas no ParamétricasRESUMEN
BACKGROUND: Malignant mesothelioma (MM) is a highly aggressive tumour with poor prognosis and limited response to therapy. New markers for the prediction of prognosis in MM and in pulmonary adenocarcinoma of the pleura are valuable. GATA-6 belongs to a six member zinc finger transcription factor family named after their recognition motif W-GATA-R. AIM: To clarify the distribution and possible function of GATA-6 transcription factor in MM and in pleural metastasis of lung adenocarcinomas. METHODS: 63 pleural MM and 36 pleural metastatic pulmonary adenocarcinomas were studied for GATA-6 expression by immunohistochemistry using tissue microarrays. Expression of GATA-6 was examined in relation to thyroid transcription factor-1 expression, survival, proliferation and apoptosis. RESULTS: Nuclear immunoreactivity for GATA-6 was stronger and more frequent in MM than in metastatic pleural adenocarcinoma. Prognosis was better in patients with GATA-6 expression when compared to those with no GATA-6 expression (p = 0.002); in the subgroup analysis the difference was significant in epithelial and sarcomatous mesothelioma. GATA-6 was not associated with spontaneous proliferation or apoptosis of the tumour cells in situ. CONCLUSION: Results suggest that GATA-6 plays a role in pleural malignancies, predicting longer survival in subgroups of MM.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Factor de Transcripción GATA6/metabolismo , Mesotelioma/metabolismo , Neoplasias Pleurales/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Apoptosis , Proliferación Celular , Humanos , Técnicas para Inmunoenzimas , Etiquetado Corte-Fin in Situ/métodos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Mesotelioma/patología , Mesotelioma/cirugía , Proteínas de Neoplasias/metabolismo , Neoplasias Pleurales/patología , Neoplasias Pleurales/cirugía , Pronóstico , Análisis de Supervivencia , Células Tumorales CultivadasRESUMEN
Conventional cytogenetic analyses and comparative genomic hybridization have revealed a complex and even chaotic nature of chromosomal aberrations in pleural malignant mesothelioma (MM). We set out to describe the complex gene copy number changes and screen for novel genetic aberrations using a high-density oligonucleotide microarray platform for comparative genomic hybridization (aCGH) of a series of 26 well-characterized MM tumor samples. The number of copy number changes varied from zero to 40 per sample. Gene copy number losses predominated over gains, and the most frequent region of loss was 9p21.3 (17/26 cases), the locus of CDKN2A and CDKN2B, both known to be commonly lost in MM. The most recurrent minimal regions of losses were 1p31.1--> p13.2, 3p22.1-->p14.2, 6q22.1, 9p21.3, 13cen-->q14.12, 14q22.1-->qter, and 22qcen-->q12.3. Previously unreported gains included 9p13.3, 7p22.3-->p22.2, 12q13.3, and 17q21.32-->qter. The results suggest that gene copy number losses are a major mechanism of MM carcinogenesis and reveal a recurrent pattern of copy number changes in MM.
Asunto(s)
Dosificación de Gen/genética , Mesotelioma/genética , Neoplasias Pleurales/genética , Genoma Humano/genética , Humanos , Mesotelioma/clasificación , Mesotelioma/patología , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Pleurales/clasificación , Neoplasias Pleurales/patologíaRESUMEN
OBJECTIVE: Peroxiredoxins are antioxidant enzymes (AOEs), which are redox-regulated thiol proteins with potential effects on the growth, invasion and drug resistance of neoplastic cells. In this study, their biology and clinical significance were examined in pilocytic astrocytomas (PAs). MATERIAL AND METHODS: The expression of peroxiredoxins (Prx I-VI) was investigated in 105 PAs by the means of immunohistochemistry and compared with the expression of selected other antioxidant enzymes, cell proliferation, angiogenesis, apoptosis, p53, histopathology and patient survival. RESULTS: Peroxiredoxins were strongly expressed in general suggesting that oxidative damage and consequent defense takes place during the progression of pilocytic astrocytomas. In agreement with this hypothesis, several other AOEs correlated with the degenerative features and angiogenesis possibly associated with reactive oxygen species-derived cellular damage. Moreover, the expression of the AOEs was associated with each other indicating a concurrent activation of the enzymes. With the exception of manganese superoxide dismutase (MnSOD), a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval while other AOEs had no association with patient survival. Many AOEs, such as MnSOD, induce chemo- and radioresistance and are highly elevated in aggressive malignancies. PAs lack this confounding factor, and these tumors are treated only by surgery. CONCLUSIONS: Taken together, the results of this study on pilocytic astrocytomas suggest that the levels of Prxs and other AOEs and their related thiol proteins are generally strongly expressed in these tumors. At least Prx VI can contribute to tumor behavior which can make it a potential prognostic factor.
Asunto(s)
Astrocitoma/enzimología , Astrocitoma/patología , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Peroxidasas/metabolismo , Adolescente , Adulto , Anciano , Apoptosis/fisiología , Astrocitoma/mortalidad , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Femenino , Glutamato-Cisteína Ligasa/metabolismo , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Peroxiredoxina VI , Peroxirredoxinas , Pronóstico , Superóxido Dismutasa/metabolismo , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Tiorredoxinas/metabolismoRESUMEN
The Finnish National Prevention and Treatment Programme for Chronic Bronchitis and COPD, launched in 1998, has, to date, been running for 6 years (2003). The goals of this action programme were to reduce the incidence of COPD and the number of moderate and severe cases of the disease, and to reduce both the number of days of hospitalisation and treatment costs. A prevalent implementation of over 250 information and training events started. Health centres and pharmacies appointed a person in charge of COPD patients. In order to improve the cooperation between primary and specialised care, two thirds of hospital districts created local COPD treatment chains. The early diagnosis of COPD by spirometric examination was activated during the programme. Number of health centres with available spirometric services increased to 95%. Before the start of the programme, approximately 5-9% of the adult population had COPD. During the whole programme, the proportion of male and female smokers decreased from 30% to 26% and from 20% to 19%, respectively. The total number of hospitalisation periods and days due to COPD decreased by 15% and 18%, respectively. Both the number of pensioners and daily sickness days due to COPD also decreased by 18%. Registered COPD induced deaths remained at their previous levels during the monitoring period, i.e. around 1000 deaths out of 5.2 millions annually. The measures recommended by the programme have been widely introduced but they need to be still more effective.
Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/terapia , Bronquitis Crónica/diagnóstico , Bronquitis Crónica/epidemiología , Bronquitis Crónica/terapia , Prestación Integrada de Atención de Salud/organización & administración , Diagnóstico Precoz , Femenino , Finlandia/epidemiología , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Prevalencia , Evaluación de Programas y Proyectos de Salud , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Fumar/epidemiología , Fumar/terapia , Espirometría/normas , Contaminación por Humo de Tabaco/estadística & datos numéricosRESUMEN
The lung is a unique organ in terms of its direct exposure to high levels of oxygen and reactive compounds. Several parenchymal lung diseases (e.g. emphysema associated with smoking and a number of fibrotic lung disorders) have been proposed to be due to the exposure of the lung to exogenous irritants leading to local redox imbalance in the alveolar epithelium. The disease progression of emphysema/chronic obstructive pulmonary disease (COPD) and fibrosis share several common factors, such as the role of reactive oxygen species, disturbances of the pulmonary thiol status and activation of growth factors and tissue destructing proteases. Importantly in COPD or fibrosis, medication does not provide any significant therapeutic effect. This review concentrates on the key thiol (-SH)-regulated mechanisms leading to the development of COPD and/or pulmonary fibrosis and the major redox-regulated defense/oxidant repair mechanisms, thioredoxin/peroxiredoxin and glutaredoxin protein families in the lung. Redox-regulated proteins, both proteases and oxidant repair enzymes, undergo conformational changes during oxidative stress, a process that modulates their activation or inactivation. In addition, some of the redox-regulated proteins influence the metabolism of glutathione (GSH), a major small molecular antioxidant of human lung, and participate in the crosstalk between numbers of GSH associated enzymes functioning in the detoxification pathways of human lung. An understanding of the processes involved in oxidant-mediated lung damage may provide the key to devising interventional strategies that can actually prevent the progression of lung parenchymal disease.
Asunto(s)
Enfermedades Pulmonares/etiología , Proteínas/metabolismo , Compuestos de Sulfhidrilo/metabolismo , Enfisema/etiología , Enfisema/metabolismo , Enfisema/patología , Fibrosis/etiología , Fibrosis/metabolismo , Fibrosis/patología , Humanos , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/patología , Oxidación-Reducción , Estrés Oxidativo , Proteínas/química , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patologíaRESUMEN
8-Isoprostane is a potential in vivo marker for oxidant burden, but its usefulness in induced sputum of smokers and chronic obstructive pulmonary disease (COPD) has not been investigated. The current study investigated 58 subjects comprising 11 never-smokers, 11 ex-smokers, 13 healthy current smokers and 23 COPD with stage 0-III disease (according to the Global Initiative for Chronic Obstructive Lung Disease criteria). 8-Isoprostane was determined from induced sputum by enzyme immunoassay. Sputum 8-isoprostane levels were similar in the never-smokers and ex-smokers, but were elevated in the healthy smokers compared with nonsmokers, and in those with stage I-III COPD. Sputum 8-isoprostane levels could not differentiate nonsymptomatic smokers from those with Stage 0 COPD. There was a correlation between sputum 8-isoprostane level and lung function parameters (forced expiratory volume in one second/forced vital capacity and sputum neutrophils. In conclusion, sputum 8-isoprostane levels correlate with the severity of chronic obstructive pulmonary disease. However, they do not appear to differentiate healthy smokers from those who are at risk of developing chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease stage 0).
Asunto(s)
Dinoprost/análogos & derivados , Estrés Oxidativo/fisiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Fumar/metabolismo , Esputo/metabolismo , Biomarcadores/metabolismo , Estudios de Casos y Controles , Dinoprost/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ventilación Pulmonar/fisiologíaRESUMEN
Neutrophilic airway inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD) and correlates with disease severity. The mechanisms that determine the extent of neutrophilia could involve increased influx or prolonged survival of neutrophils. The aim of the study was to assess whether neutrophil pro-survival mechanisms are increased in the airways of subjects with COPD owing to the presence of anti-apoptotic factors in the bronchial lining fluid. Induced sputum samples were collected from 20 subjects with stable COPD, 14 healthy smokers and 14 healthy controls. Quantification of apoptotic neutrophils was based on typical morphological cell changes. Anti-apoptotic, pro-survival activity in the sputum was studied by culturing peripheral blood neutrophils with the fluid phase of induced sputum. Apoptosis was assessed both by morphology and flow cytometry using Annexin V/7-aminoactinomycin D staining. COPD patients and healthy smokers had significantly higher percentages of sputum neutrophils than healthy controls. However, there were no significant differences between the three subject groups in either the proportion of apoptotic neutrophils in sputum or the in vitro anti-apoptotic activity detected in the sputum fluid phase. In conclusion, prolonged survival of neutrophils in sputum is not a feature of chronic obstructive pulmonary disease and cannot explain the increased numbers of airway neutrophils in this disease.
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Apoptosis/fisiología , Neutrófilos/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Sistema Respiratorio/patología , Adulto , Anciano , Anexina A5/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Femenino , Citometría de Flujo , Estudios de Seguimiento , Volumen Espiratorio Forzado/fisiología , Humanos , Masculino , Persona de Mediana Edad , Activación Neutrófila/fisiología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Sistema Respiratorio/metabolismo , Fumar/fisiopatología , Esputo/metabolismoRESUMEN
AIMS: Recent studies suggest the importance of oxidant stress in the progression of pulmonary fibrosis. The aim of this study was to investigate extracellular superoxide dismutase (ECSOD), the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven idiopathic pulmonary fibrosis (IPF) related to usual interstitial pneumonia (UIP). METHODS AND RESULTS: Fibrotic areas and fibroblastic foci in UIP lungs were notable for absence of ECSOD by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of ECSOD in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense ECSOD positivity in UIP was the interstitial mast cell. In order to investigate the mechanism for ECSOD depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-alpha and transforming growth factor (TGF)-beta1; TGF-beta suggested a trend towards decreased synthesis. Patients with UIP were also assessed to determine whether this disease is associated with a naturally occurring mutation in ECSOD (Arg213Gly) which leads to a loss of tissue binding of ECSOD. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 UIP patients and 61 control subjects. CONCLUSION: Overall, consistent with several other antioxidant enzymes, ECSOD is very low in fibrotic areas of UIP, which may further increase the oxidant burden in this disease.
Asunto(s)
Enfermedades Pulmonares Intersticiales/enzimología , Enfermedades Pulmonares Intersticiales/patología , Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/patología , Superóxido Dismutasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Secuencia de Bases , Estudios de Casos y Controles , Línea Celular , ADN/genética , Femenino , Variación Genética , Genotipo , Humanos , Inmunohistoquímica , Pulmón/enzimología , Enfermedades Pulmonares Intersticiales/genética , Masculino , Persona de Mediana Edad , Oxidantes/metabolismo , Fibrosis Pulmonar/genética , Superóxido Dismutasa/genéticaRESUMEN
BACKGROUND: Fibroblastic focus (FF) is the typical histopathological feature of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). A study was undertaken to analyse FF at diagnosis, to analyse the histopathological findings at necropsy, and to examine their association with the course of the disease. METHODS: A retrospective study was made of 76 UIP cases collected over a period of 30 years from one university hospital; 64 had idiopathic IPF. The surface area of one slide of each lung biopsy specimen was defined by image analysis and the total number of FF was quantified. The histological features of necroscopic lung samples were re-analysed in 11 cases. Clinical follow up information was obtained from the registers. RESULTS: Patients with < or =50 FF/cm(2) (n = 34) in the lung biopsy specimen had a median survival of 89 months (95% CI 38 to 140) compared with 49 months (95% CI 36 to 62) in those with >50 FF/cm(2) (n = 42, p = 0.0358). Diffuse alveolar damage (DAD) was detected in 10 necropsy samples and almost prevented the histopathological confirmation of UIP in six cases. Accumulation of neutrophils occurred in nine cases. There was no association between FF at diagnosis and DAD at necropsy, or between FF and exacerbation of the disease before death. CONCLUSIONS: The number of FF in lung samples before death is associated with poor survival but not with DAD, which is a common feature in necropsy specimens of patients with UIP. FF cannot predict an acute exacerbation of IPF.
Asunto(s)
Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Fibrosis Pulmonar/patología , Adulto , Anciano , Biopsia/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Peroxiredoxins (Prxs) 1-6 were assessed in 138 renal cell carcinomas (RCC) using immunohistochemistry and selected samples by Western blotting analysis. Oxidative/nitrosative damage was evaluated using nitrotyrosine immunoreactivity. The expressions of Prxs were correlated with tumor grade and survival and nitrotyrosine reactivity. Non-malignant kidney tubular cells showed positivity with variable intensity for all six Prxs. In RCCs, most cases were positive for Prxs 1 and 2, while only 15-20% of tumors showed expression for Prxs 3 and 4. Prx 2 was associated with tumors of a lower grade (p=0.009) and with a lower frequency of distant metastases (p=0.046). Patients with tumors expressing Prx2 had better prognosis (p=0.027). Instead, nitrotyrosine was significantly associated with high grade tumors (p=0.001). Compared with the non-malignant kidney tubular cells, low Prx expression in the tumor cells can make them more susceptible to oxidative damage. Prx 2 was more abundantly expressed in low grade tumors, suggesting that this protein could play a role in preventing the development of oxidative damage, which in turn can lead to the activation of pathways leading to aggressive tumors.
Asunto(s)
Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/diagnóstico , Neoplasias Renales/metabolismo , Estrés Oxidativo , Peroxidasas/metabolismo , Tirosina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Western Blotting , Carcinoma de Células Renales/patología , Humanos , Inmunohistoquímica , Neoplasias Renales/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Nefrectomía , Peroxidasas/análisis , Peroxirredoxinas , Pronóstico , Análisis de Supervivencia , Tirosina/análisis , Tirosina/metabolismoRESUMEN
Cigarette smoke causes significant oxidant stress which is further enhanced by recruitment and activation of inflammatory cells to the lung. Polymorphisms in some detoxification enzymes are thought to increase the risk of developing chronic obstructive pulmonary disease (COPD), but the ultimate role of genetic variability in antioxidant and/or detoxification enzymes in COPD remains obscure. Some antioxidant enzymes are inducted, but the extent of induction is insufficient to protect the lung/alveolar epithelium against cigarette smoke. Exogenous antioxidants such as vitamins do not seem to protect against cigarette smoke related lung injury. Glutathione related synthetic drugs such as N-acetylcysteine have shown some benefits, but they may have pro-oxidant side effects. Synthetic compounds with superoxide dismutase and catalase activities have shown promising results in animal models against a variety of oxidant exposures including cigarette smoke in the lung. These results are in agreement with studies highlighting the importance of alveolar antioxidant protection mechanisms in oxidant stress and their inducibility. These new drugs need to be tested in cigarette smoking related lung injury/inflammation since inflammation/oxidant stress can continue after discontinuation of smoking.
Asunto(s)
Antioxidantes/uso terapéutico , Enfermedades Pulmonares/enzimología , Fumar/efectos adversos , Antioxidantes/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Enfermedades Pulmonares/genética , Estrés Oxidativo/genética , Estrés Oxidativo/fisiología , Polimorfismo Genético , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Enfermedad Pulmonar Obstructiva Crónica/genética , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Oxidant stress is a key mechanism for smoking-induced chronic obstructive pulmonary disease (COPD). Smoking has been shown to upregulate several antioxidant enzymes, with potential effects on the prevention of the disease and/or its progression. Superoxide dismutases (SOD)s are the only enzymes capable of consuming superoxide radicals. The purpose of the present study was to investigate SODs in the lungs of nonsmokers, smokers and COPD patients. Manganese superoxide dismutase (MnSOD), copper zinc SOD (CuZnSOD), and extracellular SOD (ECSOD), were investigated by immunohistochemistry in the airways of 13 nonsmokers, 20 smokers and 22 COPD patients with mild-to-moderate disease. Lung tissue homogenates of three nonsmokers and four smokers were used for Western blot and enzyme activity analysis. The expression of MnSOD was higher in the central bronchial epithelium of smokers with COPD and in the alveolar epithelium of smokers without or with COPD than innonsmokers. Lung MnSOD immunoreactivity, evaluated by Western blotting and specific activity, were 33% and 51% higher, respectively, in smokers than in nonsmokers. No major changes could be observed in lung CuZnSOD or ECSOD immunoreactivities. Manganese superoxide dismutase is elevated in the alveolar epithelium of cigarette smokers, probably due to the increased oxidant burden in smokers' lungs.
Asunto(s)
Pulmón/enzimología , Fumar/metabolismo , Superóxido Dismutasa/análisis , Anciano , Aldehídos/análisis , Western Blotting , Bronquios/enzimología , Epitelio/enzimología , Femenino , Humanos , Inmunohistoquímica , Masculino , Alveolos Pulmonares/enzimología , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Fumar/efectos adversosRESUMEN
BACKGROUND: Functional polymorphisms in the genes encoding superoxide dismutases (SOD)-that is, superoxide scavenging antioxidant enzymes-may play an important role in the development of inflammatory airway diseases such as asthma. METHODS: The allele frequencies of two missense polymorphisms of SOD genes (Ala16Val in MnSOD (SOD2) and Arg213Gly in ECSOD (SOD3)) were investigated in Finnish patients with asthma and compared with family based controls. Both variants have been shown to be functionally interesting in the lung. The polymorphism at the exon-intron 3 boundary of a third SOD, CuZnSOD (SOD1), was also included in the analysis. RESULTS: None of the SOD genetic variants studied appeared to be major genetic regulators in the development of asthma. We could exclude all models of inheritance that increased the risk of asthma more than 1.2 fold for MnSOD*Val (frequency of allele 0.74 in the population) and more than 6.6 fold for ECSOD*Gly213 (frequency of allele 0.03 in the population) compared with non-carriers. For the intronic polymorphism in CuZnSOD, a relative risk of more than 3.3 (frequency of allele 0.10 in the population) could be excluded. CONCLUSIONS: It is highly unlikely that the functionally important genetic variants Ala16Val and Arg213Gly of SODs play a major role in the genetic susceptibility of asthma.
Asunto(s)
Asma/genética , Mutación Missense/genética , Superóxido Dismutasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asma/enzimología , Niño , Preescolar , Femenino , Finlandia , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo Genético/genéticaRESUMEN
AIMS: Tenascin-C is an extracellular matrix glycoprotein known to have anti-adhesive characteristics and to be expressed in various human malignant neoplasms. We hypothesized that the expression of tenascin-C would be increased in human malignant pleural mesothelioma, and its accumulation associated with the prognosis of the patients with this disease. METHODS AND RESULTS: Thirty-seven cases of mesothelioma were studied by immunohistochemically using a monoclonal antibody against tenascin-C, and with a semiquantitative scoring system for tenascin-C in different areas of the tumours. In 10 selected cases tenascin-C mRNA in-situ hybridization was also analysed. Since transforming growth factor-beta (TGF-beta) is known to induce both the synthesis of tenascin-C and the growth of mesotheliomas, an immunohistochemical analysis of TGF-beta 1, -beta 2 and -beta 3 was also performed. Normal pleura (n = 7) and metastatic pleural adenocarcinomas (n = 7) were used as controls. Tenascin-C protein was expressed in every histological subtype of malignant mesothelioma, being most prominent in the fibrotic stroma of a tumour, around tumour cells and at the invasive border, whereas tenascin-C mRNA was scarce in tumour cells. The patients with less immunohistochemical expression for tenascin-C tended to live longer (P = 0.028 by Fishers' exact probability test). All mesotheliomas showed positivity for at least one isoform of TGF-beta. CONCLUSIONS: In conclusion, high expression of tenascin-C protein in malignant pleural mesotheliomas may play a role in its invasive growth, and might serve as a prognostic marker of the disease.
Asunto(s)
Mesotelioma/metabolismo , Neoplasias Pleurales/metabolismo , Tenascina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Hibridación in Situ , Masculino , Mesotelioma/genética , Mesotelioma/patología , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Pronóstico , ARN Mensajero/metabolismo , ARN Neoplásico/análisis , Tenascina/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The purpose of this study was to evaluate the change, over 20 yrs, in the survival of lung cancer patients in a population-based study. Information on all patients with lung cancer in a defined geographical area during 1990-1992 (n=602) was prospectively gathered. The survival of these patients was assessed and also compared with the results of a similar study in the same area during the years 1968-1971 (n=446). The 5-yr survival had improved during 20 yrs from 4% to 12%. The 5-yr survival of the patients with squamous cell carcinoma had increased from 6% to 16%, and adenocarcinoma from 4% to 19%, whereas the survival of small cell carcinoma had remained the same (2% and 3%, respectively). Even though the recent patients were older than those of the earlier series the proportion of surgically treated patients had remained the same (16% and 20%), but the 5-yr survival of patients who had been operated on had increased significantly from 23% to 48%. The differences in survival in the second cohort (1990-1992) between histological types (Chi-squared logrank=59.2), tumour, node, metastasis stages (Chi-squared logrank=199.6), symptomatic stages (Chi-squared logrank=120, p<0.001) and treatment (Chi-squared logrank=277) were significant. Based on this study the independent prognostic factors for better survival of lung cancer patients are tumour, node, metastasis stages I and II, surgical treatment and Feinstein's symptomatic stages I and II.
Asunto(s)
Adenocarcinoma/mortalidad , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Escamosas/mortalidad , Neoplasias Pulmonares/mortalidad , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Anciano , Carcinoma de Células Pequeñas/secundario , Carcinoma de Células Pequeñas/terapia , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/terapia , Femenino , Humanos , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
Exhaled carbon monoxide (CO), which has been found to be elevated in asthma, is generated primarily by heme oxygenase I (HO-I), an enzyme induced by oxidant stress and cytokines. The aim of this study was to assess the distribution and expression of HO-I in various human lung cells in acute and stable asthma. Normal lung tissue biopsies (from 6 non-smoking subjects operated on for a lung tumour) and macrophages from induced sputum (from 5 healthy controls, 5 untreated asthmatics, 7 stable treated asthmatics and 5 asthmatics recovering from exacerbation and being on systemic steroids) were investigated for HO-I by immunohistochemistry. The time response of HO-I induction was examined in cultured monocytes, which are known to maturate into monocyte-derived macrophages in culture. Lung biopsies showed prominent HO-I immunoreactivity only in alveolar macrophages. Macrophages in the induced sputum of healthy controls showed no HO-I immunoreactivity, with the exception of one case. Moderate or intense HO-I immunoreactivity could be observed in alveolar macrophages in 4/5 cases with recent asthma, and 2/7 with stable asthma, but in none ofthe patients treated with systemic corticosteroids for acute exacerbation. Experiments with cultured cells revealed that HO-I was induced by oxidants within the first 24 h, but the induction was reversed during the next 48 h. HO-I is mainly expressed in alveolar macrophages of human lung. Macrophages of induced sputum show prominent but transient HO-I immunoreactivity, in untreated asthmatics, but not in asthmatics treated with corticosteroids.