Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
1.
Occup Environ Med ; 71(4): 234-40, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24213563

RESUMO

OBJECTIVES: We evaluated interactions between SERPINA1 PiMZ genotype, associated with intermediate α1-antitrysin deficiency, with outdoor particulate matter ≤10 µm (PM10), and occupational exposure to vapours, dusts, gases and fumes (VGDF), and their effects on annual change in lung function. METHODS: Pre-bronchodilator spirometry was performed in 3739 adults of the Swiss Cohort Study on Air Pollution and Lung Disease in Adults (SAPALDIA) for whom SERPINA1 genotypes were available. At baseline in 1991, participants were aged 18-62 years; follow-up measurements were conducted from 2001 to 2003. In linear mixed regression models of annual change in lung function, multiplicative interactions were evaluated between PiMZ genotype (PiMM as reference) and change in PM10 (µg/m(3)), and VGDF exposure (high-level, low-level or no exposure as reference) during follow-up. RESULTS: Annual declines in forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%) (-82 mL/s, 95% CI -125 to -39) and forced expiratory volume in 1 s over forced vital capacity (FEV1/FVC) (-0.3%, 95% CI -0.6% to 0.0%) in association with VGDF exposure were observed only in PiMZ carriers (Pinteraction<0.0001 and Pinteraction=0.03, respectively). A three-way interaction between PiMZ genotype, smoking and VGDF exposure was identified such that VGDF-associated FEF25-75% decline was observed only in ever smoking PiMZ carriers (Pinteraction=0.01). No interactions were identified between PiMZ genotype and outdoor PM10. CONCLUSIONS: SERPINA1 PiMZ genotype, in combination with smoking, modified the association between occupational VGDF exposure and longitudinal change in lung function, suggesting that interactions between these factors are relevant for lung function decline. These novel findings warrant replication in larger studies.


Assuntos
Genótipo , Pneumopatias/genética , Pulmão/fisiopatologia , Doenças Profissionais/genética , Exposição Ocupacional/efeitos adversos , Material Particulado/efeitos adversos , alfa 1-Antitripsina/genética , Adolescente , Adulto , Poluição do Ar/efeitos adversos , Estudos de Coortes , Poeira , Feminino , Seguimentos , Volume Expiratório Forçado , Gases , Predisposição Genética para Doença , Humanos , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/etiologia , Doenças Profissionais/fisiopatologia , Fumar/efeitos adversos , Espirometria , Suíça , Capacidade Vital , Adulto Jovem , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genética
3.
Pathologica ; 102(6): 547-56, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21428118

RESUMO

Pulmonary alveolar proteinosis (PAP), lymphangioleyomiomatosis (LAM) and amyloidosis are three unrelated diseases of rare occurrence, with characteristic histopathological features. A pattern of alveolar filling with granular pink material accumulation is characteristic of PAP. This material can be recognized in lung biopsies, but also in bronchial lavage fluid. PAP is clinically related to the abnormal clearance of alveolar surfactant, most commonly due to the disruption of the granulocyte macrophage-colony stimulating factor signalling pathway. Whole lung lavage is the treatment of choice. LAM is characterized by cystic lung degeneration and interstitial proliferation of LAM cells, which express both melanocyte and smooth muscle cell markers, has a typical cystic pattern on CT scan, can be associated clinically with abdominal angiomyolipomas and limphangioleiomyomas, and occurs in female patients, either in isolation or as a manifestation of tuberous sclerosis. Sex hormone manipulation is the therapy of choice in this otherwise progressive disease. Diffuse interstitial or perivascular amyloid deposits in the lung can form in the context of systemic amyloidosis, usually associated with myeloma or monoclonal gammopathy, and less often with chronic inflammatory diseases. Nodular amyloid deposits, in contrast, are not associated with systemic lung disease, and present instrumentally as a coin lesion or lung mass. Isolated tracheobronchial amyloidosis is another rare form that is not related to systemic disease. In all conditions, amyloid has a typical waxy, amorphous, slightly eosinophilic stain, stains red with Congo red and presents a characteristic apple-green birefringence under polarized light, which is essential for diagnosis.


Assuntos
Amiloidose/diagnóstico , Pulmão/patologia , Proteinose Alveolar Pulmonar/diagnóstico , Doenças Raras/diagnóstico , Feminino , Humanos , Pneumopatias/congênito , Pneumopatias/diagnóstico , Pneumopatias/diagnóstico por imagem , Pneumopatias/terapia , Linfangiectasia/congênito , Linfangiectasia/diagnóstico , Linfangiectasia/diagnóstico por imagem , Linfangiectasia/terapia , Radiografia
4.
Eur Respir J ; 32(5): 1146-57, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18978133

RESUMO

Desmosine (DES) and isodesmosine (IDES) are two unusual, tetrafunctional, pyridinium ring-containing amino acids involved in elastin cross-linking. Being amino acids unique to mature, cross-linked elastin, they are useful for discriminating peptides derived from elastin breakdown from precursor elastin peptides. According to these features, DES and IDES have been extensively discussed as potentially attractive indicators of elevated lung elastic fibre turnover and markers of the effectiveness of agents with the potential to reduce elastin breakdown. In the present manuscript, immunology-based and separation methods for the evaluation of DES and IDES are discussed, along with studies reporting increased levels of urine excretion in chronic obstructive pulmonary disease (COPD) patients with and without alpha(1)-antitrypsin deficiency. The results of the application of DES and IDES as surrogate end-points in early clinical trials in COPD are also reported. Finally, recent advances in detection techniques, including liquid chromatography tandem mass spectrometry and high-performance capillary electrophoresis with laser-induced fluorescence, are discussed. These techniques allow detection of DES and IDES at very low concentration in body fluids other than urine, such as plasma or sputum, and will help the understanding of whether DES and IDES are potentially useful in monitoring therapeutic intervention in COPD.


Assuntos
Desmosina/sangue , Elastina/metabolismo , Doença Pulmonar Obstrutiva Crônica/sangue , Adulto , Criança , Cromatografia Líquida/métodos , Feminino , Humanos , Isodesmosina/sangue , Masculino , Modelos Biológicos , Peptídeos/química , Fumar , Espectrometria de Massas em Tandem/métodos , Deficiência de alfa 1-Antitripsina/sangue
5.
Respir Med ; 102(3): 354-8, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18396513

RESUMO

Targeted detection programmes are recommended to identify subjects affected by severe alpha1-antitrypsin deficiency (AATD). Guidelines are available to address physicians towards subjects at high risk for AATD. We wanted to investigate the clinical characteristics of subjects enrolled in the programme, who result as not being affected by severe AATD; this information is not available in the present literature. We elaborated data contained in the questionnaires accompanying the samples of 2127 Italian subjects submitted for AATD detection in a period spanning 11 years (1996-2006). A total of 588 subjects were eligible to enter this study: PI*MM subjects and subjects with intermediate AATD, referred for lung disease, were characterised by a relatively young mean age, and a high proportion (31.2% and 28.6%, respectively) were never smokers. Fifty percent or more had symptoms of chronic bronchitis, but without obstruction. Only a minority belonged to most severe GOLD stages. The mean levels of AAT varied as a function of the presence or absence of airflow obstruction in intermediate AATD subjects, but not in PI*MM. Individuals enrolled in AATD detection programmes represent an interesting cohort both for public health and research purposes.


Assuntos
Deficiência de alfa 1-Antitripsina/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pneumopatias Obstrutivas/etiologia , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Fatores de Risco , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genética
6.
Eur Respir J ; 21(3): 444-9, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12661999

RESUMO

Genetic factors are believed to play a role in the individual susceptibility to chronic obstructive pulmonary disease (COPD). Tumour necrosis factor (TNF) family genes have been widely investigated but inconsistent results may lie either in the genetic heterogeneity of populations or in the poor phenotype definition. A genetic study was performed using a narrower phenotype of COPD. The authors studied 86 healthy smokers and 63 COPD subjects who were enrolled based on irreversible airflow obstruction (forced expiratory volume in one second/forced vital capacity <70% predicted) and a diffusing capacity for carbon monoxide <50% predicted (moderate-to-severe COPD associated with pulmonary emphysema). The following polymorphisms were investigated: TNF-308, the biallelic polymorphism located in the first intron of the lymphotoxin-alpha gene, and exon 1 and exon 6 of the TNF receptor 1 and 2 genes, respectively. No significant deviations were found concerning the four polymorphisms studied between the two populations. The authors confirm that the tumour necrosis factor family genes, at least for the polymorphisms investigated, are not major genetic risk factors for chronic obstructive pulmonary disease in Caucasians, either defined in terms of emphysema (this study) or airflow obstruction (previous studies). Nevertheless, the authors would like to emphasise the importance of narrowing the phenotype in the search for genetic risk factors in chronic obstructive pulmonary disease.


Assuntos
Predisposição Genética para Doença , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Fator de Necrose Tumoral alfa/genética , Idoso , Sequência de Bases , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , Reação em Cadeia da Polimerase , Probabilidade , Doença Pulmonar Obstrutiva Crônica/complicações , Enfisema Pulmonar/complicações , Receptores do Fator de Necrose Tumoral/genética , Valores de Referência , Testes de Função Respiratória , Índice de Gravidade de Doença
7.
Eur Respir J ; 19(6): 1128-35, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12108868

RESUMO

Previous studies have shown that surfactant apoprotein A (SP-A) and natural or synthetic surfactant can modulate the release of pro-inflammatory cytokines from alveolar mononuclear phagocytes. The aim of this study was to assess whether SP-A or Surfactant (Surf) from patients with pulmonary alveolar proteinosis (PAP) can affect the release of two chemokines (interleukin (IL)-8 and monocyte chemtactic peptide (MCP)-1) from human monocytes and rat lung type-II cells. In addition IL-8 and MCP-1 levels were assessed in the brochoalveolar lavage fluid (BALF) of seven patients with PAP and compared with those in a group of control subjects (n=5). SP-A, tested over a wide range of concentrations, significantly increased IL-8 and MCP-1 release from monocytes. SP-A retained its activity after collagenase digestion, but was not active after heat treatment. The release of IL-8 by monocytes was also stimulated by Surf. Finally, median BALF IL-8 and MCP-1 levels in PAP patients were significantly higher than in controls (9.50 and 9.51 pg x mL(-1) in controls versus 151.95 and 563.70 pg x mL(-1) in PAP, respectively) and significantly correlated with SP-A concentrations in BALF. Overall the results of this study support the view that the high content of alveolar surfactant apoprotein A may contribute to the upregulation of chemokine release in pulmonary alveolar proteinosis, thus contributing to airway inflammation.


Assuntos
Quimiocina CCL2/biossíntese , Interleucina-8/biossíntese , Proteinose Alveolar Pulmonar/metabolismo , Proteína A Associada a Surfactante Pulmonar/farmacologia , Adulto , Animais , Líquido da Lavagem Broncoalveolar/química , Células Cultivadas , Quimiocina CCL2/análise , Feminino , Humanos , Interleucina-8/análise , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Proteinose Alveolar Pulmonar/imunologia , Ratos , Mucosa Respiratória/citologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo
8.
Am J Respir Cell Mol Biol ; 25(4): 492-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11694455

RESUMO

Fourteen-member-ring macrolides are antibiotics with a variety of anti-inflammatory activities, and have repeatedly been reported to reduce mucus hypersecretion in conditions such as cystic fibrosis and bronchiectasis. Their structure is characterized by a macrocyclic lactone ring. Because human neutrophil elastase (HNE) plays a crucial role in the vicious circle leading to mucus hypersecretion, and lactones are known to be elastase inhibitors, we hypothesized that macrolides might directly inhibit elastase. To investigate this hypothesis we designed a series of spectrophotometric experiments using a chromogenic substrate with two macrolides, erythromycin (Er) and flurythromycin (FE). We determined the 1st order rate constant (k(obs)) by inhibition and competitive substrate assays, the latter allowing us to calculate the substrate binding constant or inhibition constant and the acylation rate constant (k(a)). A proflavine displacement assay was used to determine the deacylation rate constant (k(d)). Both Er and FE are good HNE inhibitors, showing a high k(a) and a low k(d). Because the number of turnovers per inactivation of Er was congruent with 20-fold higher than that of FE, we supposed that the lower reactivation of HNE-FE was due to the formation of a more stable inactivated enzyme. This hypothesis was confirmed by the hydrazine reactivation of the acyl enzyme. For Er we identified a k(d) only, whereas for FE, in addition to the k(d), an alkylation constant (k(2)) was calculated, correlated to a fully inactivated enzyme. From our kinetics data, we therefore conclude that Er acts as an alternate substrate HNE inhibitor, whereas FE acts as an inactivator.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Eritromicina/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Acilação , Bioquímica/métodos , Ativação Enzimática/efeitos dos fármacos , Eritromicina/análogos & derivados , Humanos , Relação Estrutura-Atividade
9.
Am J Respir Crit Care Med ; 162(6): 2069-72, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11112116

RESUMO

We evaluated the ability of intravenous supplementation therapy with alpha(1)-antitrypsin (AAT) to reduce the rate of urinary excretion of desmosine (DES), a specific marker of elastin degradation, in eight men and four women with emphysema due to severe, congenital deficiency of AAT (range 17-69 mg/dl). Nine were former cigarette smokers, two were current smokers, and one reported never smoking; their mean age was 54 (SD 12) yr and their mean FEV(1) was 41 (18%) of predicted. Urinary DES was measured by isotope dilution and HPLC. Prior to the start of AAT supplementation, mean DES excretion was 13.0 (5.0) microg/g creatinine, 73% higher than in healthy nonsmokers. During 8 wk of supplementation therapy, mean urinary DES excretion was 13.0 (5.9) microg/g creatinine, unchanged from the baseline period (p = 0.85 by repeated measures ANOVA). We conclude that baseline levels of elastin degradation in emphysematous patients with severe AAT deficiency were abnormally high and that 8 wk of AAT supplementation therapy did not appreciably reduce the rate of elastin degradation. These findings raise the possibilities that protective levels of AAT in the lungs are insufficient or that elastin degradation in the lungs of these subjects is not dependent upon neutrophil elastase at this time.


Assuntos
Elastina/metabolismo , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , alfa 1-Antitripsina/administração & dosagem , Doença Aguda , Adulto , Análise de Variância , Cotinina/urina , Desmosina/urina , Feminino , Humanos , Infusões Intravenosas , Pulmão/metabolismo , Masculino , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/etiologia , Enfisema Pulmonar/metabolismo , Fatores de Tempo , alfa 1-Antitripsina/análise , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/congênito , Deficiência de alfa 1-Antitripsina/metabolismo
10.
Eur Respir J ; 16(4): 768-80, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11106224

RESUMO

Sarcoidosis is an immune-mediated, multiorgan, granulomatous disorder thought to be triggered by an intricate combination of environmental and genetic factors. Two robust lines of evidence support the hypothesis of a genetic component in the pathogenesis of sarcoidosis: racial variation in its epidemiology and familial clustering of cases. The relationship between epidemiology and environmental factors affecting variations in sarcoidosis incidence/prevalence and presentation are reviewed, as well as strategies to be pursued in the search for susceptibility genes for the disorder. Pathogenic processes leading to sarcoid granuloma formation and maintenance have prompted investigators interested in the genetics of sarcoidosis to focus mainly on major histocompatibility complex genes, and indeed a remarkable amount of data has been accumulated during the last two decades. Whilst in contrast with some autoimmune disorders a clear association between human leukocyte antigen (HLA) and sarcoidosis is still a controversial issue, there is, however, a general agreement that some HLA genes are related to phenotypic variations of the disease. Some genetic investigators have focused on T-cell receptor genes, immunoglobulin genes, angiotensin converting enzyme gene, chemokine genes and others. From a review of studies performed in different racial and ethnic groups, a reasonable suggestion arises that genetic factors are the major determinant in the racial variations in the epidemiology of the disorder. This assumption is, however, so far limited by lack of studies considering both genetic and environmental factors simultaneously.


Assuntos
Sarcoidose/genética , Exposição Ambiental , Humanos , Fatores de Risco , Sarcoidose/epidemiologia
11.
Eur J Hum Genet ; 8(9): 717-20, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10980579

RESUMO

A complete screening of the CFTR gene by DGGE and DNA sequencing was performed in patients with sarcoidosis. In 8/26 cases, missense and splicing CFTR gene mutations were found, a significant difference over controls (9/89) from the same population (P = 0.014). The odds ratio for a person with a CFTR gene mutation to develop the disease is 3.95 (1.18 < OR < 13.26). Seven different CFTR gene mutations were observed: R75Q, R347P, 621 + 3 A/G, 1898 + 3 A/G, L997F, G1069R, and a novel mutation which was detected in this study, I991V. R75Q mutation was present in 3/26 patients, a significant increase (P = 0. 01) in cases over controls, indicating its preferential association with sarcoidosis. A trend towards disease progression was observed in patients with CFTR gene mutations compared to patients without mutations. These data suggest that CFTR gene mutations predispose to the development of sarcoidosis.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Frequência do Gene , Mutação , Sarcoidose Pulmonar/genética , Adulto , Processamento Alternativo , Estudos de Casos e Controles , Fibrose Cística/epidemiologia , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Fenótipo , Isoformas de Proteínas/genética , Sarcoidose Pulmonar/epidemiologia
12.
Eur Respir J ; 16(1): 74-80, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10933088

RESUMO

The aetiology of sarcoidosis is still unknown. Environmental exposures are believed to interact with genetic factors in determining the pattern of sarcoidosis presentation, progression and prognosis. The frequency of serological polymorphism of immunoglobulin G heavy chain (Gm) and kappa light chain (kappam) markers in 107 patients with biopsy-proven sarcoidosis and in 227 controls, and their interactions with histocompatibility leukocyte antigen (HLA) class I, II, and III markers, were studied. A "protective" effect of the Gm(3 5*) phenotype in the sarcoid group versus controls (p-value for number of specificities tested (p(c))=0.05, odds ratio 0.15) and a reduced frequency of Gm(3 23 5*) in patients with advanced chest radiographic stage (Chi-squared (two degrees of freedom)(chi2(2df) 17.61, p(c)=0.0058) were observed. With reference to epistatic interactions, the combination Gm(3 23 5*)/BfS had a "protective" effect towards stage II (chi2(2dt) 13.86, p(c)=0.043). Finally, correspondence analysis defined two clusters: HLA-DR4, C4BQ0, Gm(1, 3, 17 23 5*, 21, 28) and BfF associated with stage II, and HLA-DR3, C4AQ0, kappam(1) and Gm(3 23 5*) associated with stage I. These data further support the hypothesis that sarcoidosis results from an interplay of environmental factors and genes, each contributing to the susceptibility/resistance to and/or the clinical heterogeneity of the disease. In addition, these data provide the first evidence of an interaction between immunoglobulin G heavy chain/kappa light chain markers and histocompatibility leukocyte antigen class III genes in a disease.


Assuntos
Antígenos HLA/análise , Cadeias gama de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/genética , Sarcoidose Pulmonar/genética , Adulto , Epistasia Genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Polimorfismo Genético , Sarcoidose Pulmonar/imunologia
13.
Eur Respir J ; 15(6): 1039-45, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10885422

RESUMO

Degradation of extracellular matrix components is central to many pathological features of chronic destructive lung disorders. Desmosine and isodesmosine are elastin-derived cross-linked amino acids whose urine levels are considered representative of elastin breakdown. The aim of this study was to apply a novel methodology, based on high-performance capillary electrophoresis, to the quantification of desmosine and isodesmosine in 11 patients with stable chronic obstructive pulmonary disease (COPD), 10 with an exacerbation of COPD, nine with alpha1-antitrypsin deficiency, 13 with bronchiectasis, and 11 adults with cystic fibrosis, in comparison to 24 controls. It was found that, in patients with stable COPD, urinary desmosine levels were higher than in controls (p=0.03), but lower than in COPD subjects with an exacerbation (p< or =0.05). The highest desmosine levels were found in subjects with alpha1-antitrypsin deficiency, bronchiectasis and cystic fibrosis (p<0.001 versus stable COPD). In a short-term longitudinal study, five stable COPD patients showed a constant rate of desmosine excretion (mean coefficient of variation <8% over three consecutive days). In conclusion, the present method is simple and suitable for the determination of elastin-derived cross-linked amino acid excretion in urine, giving results similar to those obtained using other separation methods. In addition, evidence is presented that urinary desmosine excretion is increased in conditions characterized by airway inflammation, such as exacerbations of chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis. Results obtained in subjects with alphal-antitrypsin deficiency suggest that this method might be used to evaluate the putative efficacy of replacement therapy.


Assuntos
Desmosina/urina , Eletroforese Capilar/métodos , Isodesmosina/urina , Pneumopatias Obstrutivas/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Bronquiectasia/urina , Reagentes de Ligações Cruzadas/metabolismo , Estudos Transversais , Fibrose Cística/urina , Desmosina/análise , Elastina/metabolismo , Enfisema/urina , Matriz Extracelular/metabolismo , Feminino , Humanos , Isodesmosina/análise , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Deficiência de alfa 1-Antitripsina/urina
14.
Chest ; 117(5): 1353-8, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10807822

RESUMO

BACKGROUND: Tumor necrosis factor (TNF) is a potent proinflammatory cytokine with increased levels in the sputum of COPD subjects. Two biallelic TNF gene complex polymorphisms have been described: LtalphaNcoI, in the first intron of the lymphotoxin alpha (previously referred to as TNF-beta) gene, and TNF-308, in the promoter region of the TNF-alpha gene. Higher levels of TNF production are associated with allele 1 of LtalphaNcoI (LtalphaNcoI*1) and with allele 2 of TNF-308 (TNF-308*2). STUDY OBJECTIVES: To study the frequencies of the two TNF gene complex polymorphisms in patients with COPD and bronchiectasis. DESIGN: Association study. SUBJECTS AND METHODS: We studied the frequencies of these polymorphisms in 66 subjects with COPD and in 23 subjects with disseminated bronchiectasis and compared them to the frequencies in 98 healthy control subjects and 45 subjects with nonobstructive pulmonary disease. Genomic DNA samples were extracted, and TNF-alpha and LtalphaNcoI polymorphisms were detected after polymerase chain reaction by restriction digestion. RESULTS: We found the following frequencies: the TNF-308*2 allele was detected in 11% of COPD individuals, 15% of bronchiectasis patients, 10% of healthy control subjects, and 18% of subjects with nonobstructive pulmonary disease. The LtalphaNcoI*1 allele was detected in 28% of COPD individuals, 30% of bronchiectasis patients, 29% of healthy control subjects, and 29% of subjects with nonobstructive pulmonary disease. We found evidence of linkage disequilibrium between the two loci (Delta = 0.068). CONCLUSIONS: We conclude that the TNF gene complex, at least in Caucasoid individuals and for the considered polymorphisms, does not seem to play a major role as genetic risk factor in COPD and bronchiectasis.


Assuntos
Bronquiectasia/genética , Pneumopatias Obstrutivas/genética , Fator de Necrose Tumoral alfa/genética , Idoso , Alelos , Bronquiectasia/diagnóstico , Feminino , Frequência do Gene , Humanos , Pneumopatias Obstrutivas/diagnóstico , Linfotoxina-alfa/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética
15.
Respir Med ; 93(3): 169-72, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10464873

RESUMO

alpha 1-antitrypsin (AAT) deficiency is an inherited condition characterized by low serum levels of AAT and an increased risk of developing pulmonary emphysema. The disease occurs mainly in Caucasians, but Southern Europe, including Italy, is considered a low prevalence area. We developed a national program in Italy in order to improve our knowledge of the epidemiology of AAT deficiency and to establish a registry of the AAT-deficient individuals. The program had two phases: the first lasted 36 months, during which blood from coupons mailed by respiratory physicians from throughout the country, was isoelectrofocused by the Central Laboratory in Rome. The second phase started in February 1996, and the Registry was established. Up to August 1998, 151 subjects with AAT deficiency have been identified and 64 have been enrolled in the Registry. We believe that such a program plays a crucial role in identifying AAT deficiency in a country such as Italy, with low prevalence and low awareness of this rare condition.


Assuntos
Programas de Rastreamento/organização & administração , Deficiência de alfa 1-Antitripsina/diagnóstico , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Prevalência , Desenvolvimento de Programas , Fatores de Risco , Deficiência de alfa 1-Antitripsina/epidemiologia
16.
Electrophoresis ; 20(7): 1578-85, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10424483

RESUMO

The geometry of the catalytic site of Pseudomonas aeruginosa elastase was reexamined, exploiting the specific feature of micellar electrokinetic chromatography (MEKC), i.e., its ability to detect a decrease of intact substrate and simultaneous formation of reaction products. We carried out a detailed investigation using two tri- and six tetra-peptide 4-nitroanilides (NA) differing from each other by only one or more amino acids as stable substrates. The kinetic cleavage parameters Km and k(cat) determined by MEKC and the catalytic efficiency Km/k(cat) values calculated allowed us to better define the substrate specificity of this proteinase.


Assuntos
Cromatografia Capilar Eletrocinética Micelar/métodos , Elastase Pancreática/química , Pseudomonas aeruginosa/enzimologia , Aminoácidos/análise , Sítios de Ligação , Catálise , Cinética , Espectrometria de Massas , Peptídeos/análise , Fatores de Tempo
17.
Am J Physiol ; 274(5): L737-49, 1998 05.
Artigo em Inglês | MEDLINE | ID: mdl-9612289

RESUMO

Serum lipoproteins may enter the airways and appear in sputum (chyloptysis) when the lymphatic circulation is impaired by inflammation, neoplasia, or an abnormal proliferation of smooth muscle cells. While analyzing the bronchoalveolar lavage fluid of a patient with chyloptysis, we noticed that surfactant could not be separated from contaminating serum lipoproteins and speculated that lipoproteins might interact with surfactant components. To clarify this point we immobilized surfactant protein (SP) A on microtiter wells and incubated it with 125I-labeled very low density lipoproteins (VLDLs), low-density lipoproteins, and high-density lipoproteins. We found that SP-A binds lipoproteins. Studying in greater detail the interaction of SP-A with VLDLs, we found that the binding is time and concentration dependent; is inhibited by unlabeled lipoproteins, phospholipids, and antibodies to SP-A; is increased by Ca2+; and is unaffected by methyl alpha-D-mannopyranoside. Whole surfactant is a potent inhibitor of binding. Furthermore, we found that SP-A increases the degradation of VLDLs by alveolar macrophages and favors the association of VLDLs with alveolar surfactant. We conclude that SP-A influences the disposal of serum lipoproteins entering the airways and speculate that binding to alveolar surfactant might represent an important step in the interaction between exogenous substances and the lung.


Assuntos
Quilotórax/fisiopatologia , Lipoproteínas/sangue , Lipoproteínas/metabolismo , Pulmão/metabolismo , Proteolipídeos/fisiologia , Surfactantes Pulmonares/fisiologia , Líquido da Lavagem Broncoalveolar/química , Feminino , Humanos , Lipoproteínas VLDL/metabolismo , Macrófagos Alveolares/metabolismo , Microscopia Eletrônica , Pessoa de Meia-Idade , Proteína A Associada a Surfactante Pulmonar , Proteínas Associadas a Surfactantes Pulmonares
18.
Hum Genet ; 103(6): 718-22, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9921909

RESUMO

In order to determine the possible role of the cystic fibrosis transmembrane regulator (CFTR) gene in pulmonary diseases not due to cystic fibrosis, a complete screening of the CFTR gene was performed in 120 Italian patients with disseminated bronchiectasis of unknown cause (DBE), chronic bronchitis (CB), pulmonary emphysema (E), lung cancer (LC), sarcoidosis (S) and other forms of pulmonary disease. The 27 exons of the CFTR gene and their intronic flanking regions were analyzed by denaturing gradient gel electrophoresis and automatic sequencing. Mutations were detected in 11/23 DBE (P = 0.009), 7/25 E, 5/27 CB, 5/26 LC, 5/8 S (P = 0.013), 1/4 tuberculosis, and 1/5 pneumonia patients, and in 5/33 controls. Moreover, the IVS8-5T allele was detected in 6/25 E patients (P = 0.038). Four new mutations were identified: D651N, 2377C/T, E826K, and P1072L. These results confirm the involvement of the CFTR gene in disseminated bronchiectasis of unknown origin, and suggest a possible role for CFTR gene mutations in sarcoidosis, and for the 5T allele in pulmonary emphysema.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Pneumopatias/genética , Mutação , Adulto , Idoso , Feminino , Testes Genéticos , Genótipo , Humanos , Itália/epidemiologia , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA