RESUMO
Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation. It is most likely the result of complex interactions of environmental and genetic factors. Because pulmonary surfactant components play important roles in normal lung function, innate host defence, and inflammation in the lung, this study investigated the hypothesis that the surfactant protein genes are involved in certain cases of COPD. Genotype analysis of surfactant protein (SP)-A, SP-B, SP-B-linked microsatellite, and SP-D marker alleles was performed in patients with COPD (n=97) and smoker (n=82) or nonsmoker (n=99) controls. Univariate and multiple logistic regression analyses were performed. The regression analysis results between COPD and smokers revealed several COPD susceptibility alleles (AA62_A, B1580_C, D2S388_5), based on an odds ratio (OR >2.5). The predictive ability of this model for developing COPD is good (c=0.926). Allele-allele (B1580_C and D2S388_5) and allele-environment (i.e. smoking) interactions were detected. When smoker controls were compared to nonsmoker controls, marker D2S388 5 appeared to be smoking-independent (p=0.874), whereas marker alleles AA62_A (p=0.045) and B1580_5 (p=0.007) were smoking-dependent. Males were at higher risk (OR=6.05, p=0.001), and smoking (>50 packs x yr(-1)) increased risk (OR=5.38, p=0.007). Males and alleles of loci flanking SP-B were associated with more severe cases (forced expiratory volume in one second/forced vital capacity < or = 40%). The present results indicate that the surfactant protein alleles may be useful in chronic obstructive pulmonary disease by either predicting the disease in a subgroup and/or by identifying disease subgroups that may be used for therapeutic intervention. These observations should now be confirmed in a larger study, designed according to strict epidemiological criteria.
Assuntos
Alelos , Proteínas de Transporte/genética , Glicoproteínas/genética , Precursores de Proteínas/genética , Proteolipídeos/genética , Doença Pulmonar Obstrutiva Crônica/genética , Surfactantes Pulmonares/genética , População Branca/genética , Idoso , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Fatores de Confusão Epidemiológicos , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , México/epidemiologia , Repetições de Microssatélites , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Proteína A Associada a Surfactante Pulmonar , Proteína D Associada a Surfactante Pulmonar , Proteínas Associadas a Surfactantes Pulmonares , Estudos Soroepidemiológicos , FumarRESUMO
Surfactant protein-A, which plays a role in innate host defense in the lung, is also expressed in the Eustachian tube. We report that the frequency of specific surfactant protein-A haplotypes and genotypes differs between children with recurrent otitis media compared with a control population.
Assuntos
Lectinas/genética , Otite Média/genética , Proteolipídeos/genética , Surfactantes Pulmonares/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Proteínas Associadas a Surfactantes Pulmonares , RecidivaRESUMO
Pulmonary surfactant and its components are essential for normal lung function and are involved in local host defense. Surfactant protein (SP)-A and SP-D bind to and modulate phagocytosis of Mycobacterium tuberculosis by macrophages. Frequency comparisons of SP marker alleles in tuberculosis patients and healthy control subjects (tuberculin-skin test positive or general population) were performed. Regression analyses of the tuberculosis and the tuberculin-skin test positive groups revealed, on the basis of odds ratios, tuberculosis susceptibility (DA11_C and GATA_3) and protective (AAGG_2) marker alleles. Similarly, between tuberculosis patients and general population control subjects, susceptibility 1A(3), 6A(4), and B1013_A and protective AAGG_1, and AAGG_7 marker alleles were observed. Moreover, interactions were seen between alleles 6A(2) and 1A(3) (P=.0064) and between 1A(3) and B1013_A (P=. 036). The findings indicate a possible involvement of SP alleles in tuberculosis pathogenesis.
Assuntos
Alelos , Glicoproteínas/genética , Proteolipídeos/genética , Surfactantes Pulmonares/genética , Tuberculose/genética , Adulto , Idoso , Feminino , Marcadores Genéticos , Humanos , Masculino , México , Pessoa de Meia-Idade , Proteína A Associada a Surfactante Pulmonar , Proteína D Associada a Surfactante Pulmonar , Proteínas Associadas a Surfactantes Pulmonares , Teste Tuberculínico , Tuberculose/etiologiaAssuntos
Pneumopatias Obstrutivas/genética , Repetições de Microssatélites/genética , Polimorfismo Genético , Surfactantes Pulmonares/genética , Predisposição Genética para Doença , Genótipo , Glicoproteínas/genética , Humanos , Incidência , Pneumopatias Obstrutivas/etnologia , México/epidemiologia , Proteolipídeos/genética , Proteína D Associada a Surfactante Pulmonar , Proteínas Associadas a Surfactantes Pulmonares , Fatores de Risco , Fumar/efeitos adversos , Fumar/genética , Fumar/metabolismoRESUMO
A 38-day-old male infant with persistent pulmonary hypertension and respiratory failure since birth was found to have a complete absence of surfactant protein B (SP-B) along with an aberrant form of SP-C in his tracheal aspirate fluid, findings consistent with the diagnosis of hereditary SP-B deficiency. Surprisingly, SP-B and SP-B messenger ribonucleic acid were present in lung biopsy tissue. However, DNA sequence analysis demonstrated a point mutation in exon 5 of one of the SP-B gene alleles. The infant's mother was found to be a carrier of this mutation. The infant's other SP-B allele did not differ from the published DNA sequence for the SP-B gene. We conclude that this patient had a transient deficiency of SP-B, in contrast to that of previously described infants with irreversible respiratory failure caused by hereditary SP-B deficiency. We recommend that infants with suspected SP-B deficiency have serial analysis of tracheal fluid samples for both SP-B and SP-C before lung biopsy, along with genetic analysis for the known SP-B mutations. We speculate that the new mutation found in one of this patient's SP-B genes was in part responsible for the transient deficiency of SP-B.
Assuntos
Erros Inatos do Metabolismo/genética , Proteolipídeos/metabolismo , Surfactantes Pulmonares/deficiência , Surfactantes Pulmonares/metabolismo , Síndrome do Desconforto Respiratório do Recém-Nascido/metabolismo , Exsudatos e Transudatos/química , Humanos , Immunoblotting , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/complicações , Mutação , Reação em Cadeia da Polimerase , Proteolipídeos/genética , Surfactantes Pulmonares/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Análise de Sequência de DNA , Fatores de Tempo , TraqueiaRESUMO
La ausencia de surfactantes pulmonares trae como consecuencia el incremento de la tensión superficial a lo largo del epitelio alveolar, provocando un colapso alveolar y la lisis de las células epiteliales. Este proceso culmina con la aparición de un síndrome de insuficiencia respiratoria, que es la causa principal de morbimortalidad en niños prematuros. Recientemente, la aplicación de mezclas de agentes surfactantes con fines terapéuticos ha constituido un gran apoyo para la terapia respiratoria, ya que permite una evolución más rápida de los niños que padecen este síndrome. Por todo esto, resulta de gran importancia el conocimiento más detallado de la función, el metabolismo y la regulación de la expresión genética de las proteíinas surfactantes, para el diseño de nuevas y mejores estrategias terapéuticas para combatir este síndrome
Assuntos
1,2-Dipalmitoilfosfatidilcolina/biossíntese , 1,2-Dipalmitoilfosfatidilcolina/química , Fosfolipídeos/biossíntese , Fosfolipídeos/química , Lectinas/química , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/fisiologia , Surfactantes Pulmonares/química , Surfactantes Pulmonares/genética , Surfactantes Pulmonares/ultraestruturaRESUMO
Congenital alveolar proteinosis (CAP) is an often fatal cause of respiratory failure in term newborn infants, which has been associated with a genetic deficiency of surfactant protein B (SP-B) as a result of a frameshift mutation (121ins2) in a family with three affected siblings. In the index cases the deficiency of SP-B was associated with qualitative and quantitative abnormalities of the surfactant proteins A and C. Immunostaining for lung surfactant proteins and a search for the 121ins2 mutation by restriction enzyme analysis of DNA extracted from paraffin-embedded lung tissue was performed for 7 additional affected infants from 6 families, bringing to 10 the total number of patients with CAP who have been studied. In six infants, the surfactant protein immunostaining pattern was similar to that of the index cases. Of these, three patients were homozygous for the 121ins2 mutation; one was a compound heterozygote with the 121ins2 in one allele and a different mutation in the other; and three patients lacked the mutation in both alleles. One infant had an abundance of SP-B, suggesting phenotypic heterogeneity in CAP. Lung ultrastructural abnormalities, such as a reduced number of lamellar bodies, absent tubular myelin, and basal secretion of surfactant lipids and proteins, suggest a significant derangement of surfactant metabolism. The phenotypic heterogeneity in infants with CAP raises the possibility that variable degrees of SP-B deficiency may be more common than previously suspected.
Assuntos
Pulmão/patologia , Proteolipídeos/genética , Proteinose Alveolar Pulmonar/congênito , Surfactantes Pulmonares/genética , Feminino , Mutação da Fase de Leitura , Expressão Gênica , Genótipo , Humanos , Lactente , Recém-Nascido , Pulmão/química , Pulmão/ultraestrutura , Masculino , Fenótipo , Proteolipídeos/efeitos adversos , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/patologia , Proteínas Associadas a Surfactantes Pulmonares , Surfactantes Pulmonares/efeitos adversos , Surfactantes Pulmonares/deficiênciaRESUMO
Rat surfactant protein A (SP-A) was expressed in a Chinese hamster ovary (CHO-K1) cell line and characterized for biologic activity using assays for receptor binding and modulation of phospholipid secretion from isolated type II cells. The CHO-K1 cell line was cotransfected with separate plasmids encoding for the rat SP-A, dihydrofolate reductase and neomycin phosphotransferase, respectively. Antibiotic (Geneticin-G418)-resistant transformants were screened by ELISA for the secretion of recombinant SP-A into the media. Northern analysis of the transfected cell lines demonstrated the expression of both 1.6 kb and 0.9 kb mRNA species for SP-A, consistent with the proposed differential polyadenylation of the primary transcript. Amplification with methotrexate resulted in a dose-dependent increase in mRNA for SP-A and a 20-fold increase in the production of recombinant SP-A relative to untreated cells. Maximum production of SP-A was 370 micrograms of SP-A/l of media in a 4-day incubation. Recombinant SP-A was purified from the serum-free media of large scale cultures of transfected, amplified CHO cells by affinity chromatography on mannose-Sepharose. The recombinant SP-A migrated similarly to native SP-A by NaDodSO4-PAGE analysis under reducing and nonreducing conditions and under reducing conditions after digestion with N-glycanase. Recombinant SP-A effectively competed with 125I-native SP-A for binding to the high affinity receptor for SP-A on isolated plasma membranes from rat alveolar type II cells. The recombinant SP-A was as effective as native SP-A in the inhibition of secretion of phospholipid from isolated type II cells. We conclude that recombinant rat SP-A produced in Chinese hamster ovary cells is physically and functionally similar to native rat SP-A.