RESUMO
Oxidative stress could reduce inhibitor activity of the alpha-1-antitrypsin (A1AT). Oxidative-modified A1AT (oxidized alpha-1-antitrypsin, OxyA1AT) significantly loses ability to protect the lungs from neutrophil elastase. We aimed to investigate OxyA1AT as a potential biomarker associated with onset and severity of chronic obstructive pulmonary disease (COPD) in adult population. The study included 65 patients with COPD (33 smokers and 32 no-smokers) and 46 healthy participants (17 smokers and 29 no-smokers). Determination of OxyA1AT in serum was based on the difference between the inhibitory activities of normal and oxidized A1AT against trypsin and elastase. The level of OxyA1AT was significantly increased in the group of COPD smokers compared to healthy no-smokers (p = 0.030) and COPD no-smokers (p = 0.009). The highest level of OxyA1AT was found in group of smokers with severe and very severe COPD in comparison to the following: no-smokers with the same stage of disease (p = 0.038), smokers with moderate COPD (p = 0.022), and the healthy control group, regardless of the smoking status (control no-smokers p = 0.001 and control smokers p = 0.034). In conclusion, serum level of OxyA1AT would be potentially good biomarker for the assessment of harmful effect of smoking to the onset and severity of COPD. Also, clinical significance of OxyA1AT as prognostic biomarker could be useful in assessing the effectiveness of antioxidant therapy for COPD and emphysema. Suitable and inexpensive laboratory method for determination of OxyA1AT is additional benefit for the introduction of OxyA1AT into routine clinical practice for diagnosis and monitoring of COPD.
Assuntos
Elastase de Leucócito/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , alfa 1-Antitripsina/sangue , Idoso , Análise de Variância , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Enfisema Pulmonar/etiologia , Sérvia , Índice de Gravidade de Doença , Fumar/efeitos adversos , Fumar/sangue , Estatísticas não Paramétricas , Deficiência de alfa 1-Antitripsina/complicaçõesRESUMO
Ischemia/reperfusion injury is still a major cause of morbidity and mortality during liver surgery and transplantation. A variety of surgical and pharmacological therapeutic strategies have been investigated to minimize the effects of ischemia/reperfusion. The aim of our study was to analyze and compare preventive influences of ischemic preconditioning, adenosine and prostaglandin E1 in the experimental model of hepatic ischemia/reperfusion injury. Adult chinchilla rabbits were divided into four groups: 10 rabbits subjected to liver ischemic preconditioning (3-min period of inflow occlusion followed by a 5-min period of reperfusion) followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of adenosine followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of prostaglandin E1 followed by 45 min of Pringle maneuver; and control group of 10 rabbits subjected to 45 min of inflow liver ischemia without any preconditioning. On the second postoperative day, blood samples were obtained and biochemical parameters of liver function were measured and compared. Liver tissue samples were also obtained and histopathological changes were compared. Based on biochemical and histopathological parameters, it was demonstrated that ischemic preconditioning provided the best protection against hepatic ischemia/reperfusion injury. This was probably due to a wider range of mechanisms of action of this method oriented to reduce oxidative stress and inflammation, and restore liver microcirculation and hepatocyte energy compared to the examined pharmacological strategies.
Assuntos
Adenosina/uso terapêutico , Alprostadil/uso terapêutico , Precondicionamento Isquêmico/métodos , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Animais , Chinchila , Modelos Animais de Doenças , Feminino , Fígado/efeitos dos fármacos , Fígado/patologia , MasculinoRESUMO
Ischemia/reperfusion injury is still a major cause of morbidity and mortality during liver surgery and transplantation. A variety of surgical and pharmacological therapeutic strategies have been investigated to minimize the effects of ischemia/reperfusion. The aim of our study was to analyze and compare preventive influences of ischemic preconditioning, adenosine and prostaglandin E1 in the experimental model of hepatic ischemia/reperfusion injury. Adult chinchilla rabbits were divided into four groups: 10 rabbits subjected to liver ischemic preconditioning (3-min period of inflow occlusion followed by a 5-min period of reperfusion) followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of adenosine followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of prostaglandin E1 followed by 45 min of Pringle maneuver; and control group of 10 rabbits subjected to 45 min of inflow liver ischemia without any preconditioning. On the second postoperative day, blood samples were obtained and biochemical parameters of liver function were measured and compared. Liver tissue samples were also obtained and histopathological changes were compared. Based on biochemical and histopathological parameters, it was demonstrated that ischemic preconditioning provided the best protection against hepatic ischemia/reperfusion injury. This was probably due to a wider range of mechanisms of action of this method oriented to reduce oxidative stress and inflammation, and restore liver microcirculation and hepatocyte energy compared to the examined pharmacological strategies.
Assuntos
Animais , Masculino , Feminino , Adenosina/uso terapêutico , Alprostadil/uso terapêutico , Precondicionamento Isquêmico/métodos , Hepatopatias/prevenção & controle , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Chinchila , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Fígado/patologiaRESUMO
Alpha-1-antitrypsin (AAT), an acute phase protein, is the principal circulatory anti-protease. This multifunctional protein is encoded by the SERPINA1 gene. Although AAT was recognised as a potential tumour marker, its role in cancer biology remains unknown. Given that it has been demonstrated that AAT has an anti-apoptotic property against non-malignant cells, we aimed to investigate whether AAT affects apoptosis in a colon cancer cell line (HCT116). The presence of AAT in the HCT116 cell culture antagonized cytotoxicity of blockers of MEK1/2, PI3K/Akt pathways as well as NF-κB. The dominantly recovered cell viability was observed in the co-treatment with MEK1/2 inhibitor U0126. In addition, it was revealed that AAT almost completely abolished U0126-induced apoptosis through maintenance of the autophagy process. Our study revealed for the first time that the observed cyto-protection triggered by AAT was accompanied by sustained autophagy which opposed apoptosis. These results may contribute to understanding of the role of AAT in cancer development and evaluation of efficacy of cancer therapy.
Assuntos
Butadienos/farmacologia , Neoplasias do Colo/patologia , Nitrilas/farmacologia , alfa 1-Antitripsina/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HCT116 , Humanos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismoAssuntos
Hipertensão Pulmonar/genética , Mosaicismo , Polimorfismo de Nucleotídeo Único , Protrombina/genética , Embolia Pulmonar/genética , Trombofilia/diagnóstico , Trombofilia/genética , Alanina , Biomarcadores/sangue , Cisteína , Feminino , Genótipo , Glicina , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Pessoa de Meia-Idade , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Protrombina/metabolismo , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/etiologia , Recidiva , Fatores de Risco , TreoninaRESUMO
Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as "a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF". The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR-RDs.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/classificação , Fibrose Cística/genética , Medicina/normas , Guias de Prática Clínica como Assunto , Fibrose Cística/fisiopatologia , Europa (Continente) , HumanosRESUMO
PURPOSE: Alpha-1-antitrypsin (AAT) as the major circulating inhibitor of proteases has important role in protease-antiprotease homeostasis. Recent studies have confirmed its antiapoptotic role. AAT is a highly polymorphic protein. Individuals with normal variants have normal serum levels and functional activity of ATT. However, individuals with hereditary AAT deficiency (AATD) have low circulating levels of AAT. Severe AATD was identified as genetic risk factor for early onset of pulmonary emphysema. Association between AAT phenotypes and lung cancer (LC) is not clear, and different studies show contradictory results. The aim of this case-control study was to investigate phenotypes and serum level of AAT in LC. METHODS: The study group included 147 patients with LC, classified as small cell lung cancer (SCLC, n=42) and non-small cell lung cancer (NSCLC, n=105). The control group consisted of 273 healthy blood donors. AAT phenotyping was performed by isoelectric-focusing and AAT concentration was measured using nephelometry. RESULTS: There were no differences in the frequencies of AAT phenotypes and alleles between the control group and LC patients, as well as between NSCLC and SCLC groups. An elevated level of AAT was obtained in LC patients. PiMZ and PiMS phenotypes in LC patients were not deficient in the classical sense. AAT levels were 90 and 134%, respectively, when compared to PiMM phenotype in the control group. CONCLUSION: Our findings revealed that moderate deficiency of AAT is not risk factor for LC development. Although polymorphism of AAT was not associated with risk of LC, further research of this antiprotease and antiapoptotic protein could clarify its role in carcinogenesis, given its high concentration in LC patients, even in AATD patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Carcinoma de Pequenas Células do Pulmão/sangue , Deficiência de alfa 1-Antitripsina/sangue , alfa 1-Antitripsina/sangue , alfa 1-Antitripsina/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Carcinoma de Pequenas Células do Pulmão/genética , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are a major cause of morbidity and mortality worldwide. In both diseases airways inflammation plays an important role. Functional promoter polymorphism, at the position -308, of tumor necrosis factor (TNF)-alpha represents attractive potential susceptibilty marker for both diseases. In order to investigate the role of this polymorphism in COPD and LC, a case-control study was performed. The patient groups consisted of 97 subjects with COPD and 70 subjects with LC, while the control group encompassed 102 subjects. Results of our study showed significant decrease of heterozygote for TNF-alpha-308 1/2 gene variant in COPD group in comparison to controls (p=0.043). According to our results heterozygous carriers of TNF-alpha-308 1/2 polymorphism had a2.3-fold decreased risk for COPD development (OR=0.44, 95%CI=0.20-0.97). In patients with lung cancer we also observed a trend of decreased distribution of TNF-alpha-308 1/2 heterozygotes, but statistical significance was not achieved. To our knowledge, this is the first study implicating decreased frequency of TNF-alpha-308 1/2 gene variant in patients with COPD and LC. Although these results need to be confirmed on larger cohort, they represent anew and interesting finding, not reported in other populations tested so far.
Assuntos
Neoplasias Pulmonares/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fator de Necrose Tumoral alfa/genética , Adenocarcinoma/genética , Adenocarcinoma/secundário , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/secundário , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Prognóstico , Doença Pulmonar Obstrutiva Crônica/patologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/secundárioRESUMO
Follicular lymphoma (FL) is characterized by the presence of a t(14;18) chromosomal translocation that results in overexpression of bcl-2 protein. Bcl-2/IgH gene rearrangement is detected in 80-90% of follicular lymphomas in Western countries. The aim of this study was to analyze the bcl-2/IgH rearrangement in FL lymphoma patients in Serbia, by PCR technique, correlate molecular findings with clinical characteristics and outcome and assess the prognostic significance of these rearrangements. One hundred-seven patients (median age, 54 years; male/female ratio:60/47) diagnosed with FL were included in the study. DNA samples were obtained from paraffin embedded lymphoid tissue of patients. Bcl-2/IgH rearrangement was assessed for the major breakpoint region (MBR), 5' MBR and the minor cluster region (mcr) breakpoints by PCR technique. We detected a t(14;18) in 81.3% (87/107) of patients. The distribution of bcl-2-IgH rearrangement was as follows: 88,5% (77/87) in MBR breakpoint, 10,35% (9/87) in 5' MBR, whereas mcr bcl-2-IgH rearrangement was observed in one patient (1.15%). No rearrangements were detected in remaining 20 patients (18.7%). This is the first analyses of the frequency of the bcl-2/IgH gene rearrangement in Serbian FL patients, as well as in Eastern European countries. There was no correlation between presence of bcl-2/IgH gene rearrangement and clinical outcome of disease. Incidence of bcl-2/IgH gene rearrangement in Serbian FL patients is relatively high, and similar to frequency in Western countries. Presence of this rearrangement in tumor tissue is not of prognostic significance.
Assuntos
Rearranjo Gênico de Cadeia Pesada de Linfócito B , Genes bcl-2 , Metástase Linfática , Linfoma Folicular/genética , Neoplasias Vasculares/secundário , Feminino , Genes de Imunoglobulinas , Humanos , Linfoma Folicular/diagnóstico , Masculino , Prognóstico , IugosláviaRESUMO
It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Análise Mutacional de DNA , Humanos , Estado Nutricional/genética , Polimorfismo Genético , Prognóstico , Processamento de Proteína , Controle de Qualidade , Testes de Função Respiratória , Terminologia como AssuntoRESUMO
BACKGROUND: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor alpha (TNFalpha), a member of the immune system. METHODS: Three polymorphic loci in the promoter (-851c/t, -308g/a, -238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFalpha gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients' medical records. RESULTS: An association was found between the TNFalpha +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV1) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV1 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the -851c/t polymorphic locus. In the group of patients with more severe FEV1% predicted, a higher proportion of patients were homozygous for the -851c allele than in the other group of patients (p = 0.04, likelihood ratio chi2, odds ratio = 2.4). CONCLUSION: TNFalpha polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.
Assuntos
Fibrose Cística/genética , Polimorfismo Genético/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Análise de Variância , Criança , Fibrose Cística/fisiopatologia , Feminino , Volume Expiratório Forçado/genética , Genótipo , Homozigoto , Humanos , Masculino , Mutação/genética , Fenótipo , Infecções por Pseudomonas/complicações , Pseudomonas aeruginosaAssuntos
Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/fisiologia , Polimorfismo Genético/fisiologia , Sistema Respiratório/fisiopatologia , Adolescente , Adulto , Criança , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Feminino , Humanos , Recém-Nascido , Masculino , Fenótipo , Polimorfismo Genético/genéticaAssuntos
Asma/complicações , Embolia Pulmonar/complicações , Asma/genética , Asma/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Pessoa de Meia-Idade , Embolia Pulmonar/genética , Embolia Pulmonar/fisiopatologia , Recidiva , Trombose Venosa/complicações , Trombose Venosa/fisiopatologiaRESUMO
A female patient, 28 years old, with massive haemoptysis as a complication of cystic fibrosis, is described. Cystic fibrosis is a systemic disease with common pulmonary manifestations. Chronic inflammatory process causes the proliferation of bronchial arteries, and their erosion is followed by bleeding. Transitory haemoptysis is common in patients with cystic fibrosis, but massive haemoptysis is a rare complication of this disease.
Assuntos
Fibrose Cística/complicações , Hemoptise/etiologia , Adulto , Feminino , HumanosRESUMO
A study was undertaken to find the frequency of the delta F508 deletion and those of the G551D, R553X and G524X mutations among the mainly Slavic population of Serbia, Bosnia, Herzegovina, and Montenegro and compare the frequencies determined with those in other European populations. The delta F508 mutation was found to account for about 70% of CF genes in central Jugoslavia, where its frequency is significantly higher than elsewhere in Southern European populations.