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1.
Cells ; 9(10)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019542

RESUMO

Protein degradation is important for proper cellular physiology as it removes malfunctioning proteins or can provide a source for energy. Proteasomes and lysosomes, through the regulatory particles or adaptor proteins, respectively, recognize proteins destined for degradation. These systems have developed mechanisms to allow adaptation to the everchanging environment of the cell. While the complex recognition of proteins to be degraded is somewhat understood, the mechanisms that help switch the proteasomal regulatory particles or lysosomal adaptor proteins to adjust to the changing landscape of degrons, during infections or inflammation, still need extensive exploration. Therefore, this review is focused on describing the protein degradation systems and the possible sensors that may trigger the rapid adaptation of the protein degradation machinery.

2.
Mucosal Immunol ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32690871

RESUMO

A disintegrin and metalloproteinase domain-15 (ADAM15) is expressed by cells implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), but its contributions to COPD are unknown. To address this gap, ADAM15 levels were measured in samples from cigarette smoke (CS)-versus air-exposed wild-type (WT) mice. CS-induced COPD-like disease was compared in CS-exposed WT, Adam15-/-, and Adam15 bone marrow chimeric mice. CS exposure increased Adam15 expression in lung macrophages and CD8+ T cells and to a lesser extent in airway epithelial cells in WT mice. CS-exposed Adam15-/- mice had greater emphysema, small airway fibrosis, and lung inflammation (macrophages and CD8+ T cells) than WT mice. Adam15 bone marrow chimera studies revealed that Adam15 deficiency in leukocytes led to exaggerated pulmonary inflammation and COPD-like disease in mice. Adam15 deficiency in CD8+ T cells was required for the exaggerated pulmonary inflammation and COPD-like disease in CS-exposed Adam15-/- mice (as assessed by genetically deleting CD8+ T cells in Adam15-/- mice). Adam15 deficiency increased pulmonary inflammation by rendering CD8+ T cells and macrophages resistant to CS-induced activation of the mitochondrial apoptosis pathway by preserving mTOR signaling and intracellular Mcl-1 levels in these cells. These results strongly link ADAM15 deficiency to the pathogenesis of COPD.

3.
Lung Cancer ; 146: 189-196, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32559455

RESUMO

OBJECTIVES: Smoking is a common risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Although COPD patients have higher risk of lung cancer compared to non-COPD smokers, the molecular links between these diseases are not well-defined. This study aims to identify genes that are downregulated by cigarette smoke and commonly repressed in COPD and lung cancer. MATERIALS AND METHODS: Primary human airway epithelial cells (HAEC) were exposed to cigarette-smoke-extract (CSE) for 10-weeks and significantly suppressed genes were identified by transcriptome array. Epigenetic abnormalities of these genes in lung adenocarcinoma (LUAD) from patients with or without COPD were determined using genome-wide and gene-specific assays and by in vitro treatment of cell lines with trichostatin-A or 5-aza-2-deoxycytidine. RESULTS: The ten most commonly downregulated genes following chronic CSE exposure of HAEC and show promoter hypermethylation in LUAD were selected. Among these, expression of CCNA1, SNCA, and ZNF549 was significantly reduced in lung tissues from COPD compared with non-COPD cases while expression of CCNA1 and SNCA was further downregulated in tumors with COPD. The promoter regions of all three genes were hypermethylated in LUAD but not normal or COPD lungs. The reduced expression and aberrant promoter hypermethylation of these genes in LUAD were independently validated using data from the Cancer Genome Atlas project. Importantly, SNCA and ZNF549 methylation detected in sputum DNA from LUAD (52% and 38%) cases were more prevalent compared to cancer-free smokers (26% and 15%), respectively (p < 0.02). CONCLUSIONS: Our data show that suppression of CCNA1, SNCA, and ZNF549 in lung cancer and COPD occurs with or without promoter hypermethylation, respectively. Detecting methylation of these and previously identified genes in sputum of cancer-free smokers may serve as non-invasive biomarkers for early detection of lung cancer among high risk smokers including COPD patients.

5.
J Clin Invest ; 130(2): 921-926, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31929190

RESUMO

Risk for childhood asthma is conferred by alleles within the 17q21 locus affecting ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression. ORMDL3 inhibits sphingolipid de novo synthesis. Although the effects of 17q21 genotypes on sphingolipid synthesis in human asthma remain unclear, both decreased sphingolipid synthesis and ORMDL3 overexpression are linked to airway hyperreactivity. To characterize the relationship of genetic asthma susceptibility with sphingolipid synthesis, we analyzed asthma-associated 17q21 genotypes (rs7216389, rs8076131, rs4065275, rs12603332, and rs8067378) in both children with asthma and those without asthma, quantified plasma and whole-blood sphingolipids, and assessed sphingolipid de novo synthesis in peripheral blood cells by measuring the incorporation of stable isotope-labeled serine (substrate) into sphinganine and sphinganine-1-phosphate. Whole-blood dihydroceramides and ceramides were decreased in subjects with the 17q21 asthma-risk alleles rs7216389 and rs8076131. Children with nonallergic asthma had lower dihydroceramides, ceramides, and sphingomyelins than did controls. Children with allergic asthma had higher dihydroceramides, ceramides, and sphingomyelins compared with children with nonallergic asthma. Additionally, de novo sphingolipid synthesis was lower in children with asthma compared with controls. These findings connect genetic 17q21 variations that are associated with asthma risk and higher ORMDL3 expression to lower sphingolipid synthesis in humans. Altered sphingolipid synthesis may therefore be a critical factor in asthma pathogenesis and may guide the development of future therapeutics.


Assuntos
Asma , Cromossomos Humanos Par 17 , Doenças Genéticas Inatas , Proteínas de Membrana , Esfingolipídeos/biossíntese , Adolescente , Asma/sangue , Asma/genética , Asma/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/metabolismo , Feminino , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Fatores de Risco
6.
Respir Res ; 20(1): 219, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615518

RESUMO

BACKGROUND: Plasma metabolomics profile (PMP) in COPD has been associated with clinical characteristics, but PMP's relationship to survival has not been reported. We determined PMP differences between patients with COPD who died an average of 2 years after enrollment (Non-survivors, NS) compared to those who survived (S) and also with age matched controls (C). METHODS: We studied prospectively 90 patients with severe COPD and 30 controls. NS were divided in discovery and validation cohorts (30 patients each) and the results compared to the PMP of 30 S and C. All participants completed lung function tests, dyspnea scores, quality of life, exercise capacity, BODE index, and plasma metabolomics by liquid and gas chromatography / mass spectometry (LC/MS, LC/MS2, GC/MS). Statistically, we used Random Forest Analysis (RFA) and Support Vector Machine (SVM) to determine metabolites that differentiated the 3 groups and compared the ability of metabolites vs. clinical characteristics to classify patients into survivors and non-survivors. RESULTS: There were 79 metabolites statistically different between S and NS [p < 0.05 and false discovery rate (q value) < 0.1]. RFA and SVM classification of COPD survivors and non-survivors had a predicted accuracy of 74 and 85% respectively. Elevation of tricyclic acid cycle intermediates branched amino acids depletion and increase in lactate, fructose and xylonate showed the most relevant differences between S vs. NS suggesting alteration in mitochondrial oxidative energy generation. PMP had similar predictive power for risk of death as information provided by clinical characteristics. CONCLUSIONS: A plasma metabolomic profile characterized by an oxidative energy production difference between survivors and non-survivors was observed in COPD patients 2 years before death.


Assuntos
Metabolismo Energético/fisiologia , Metabolômica/tendências , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/mortalidade , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Taxa de Sobrevida/tendências
7.
J Immunol ; 202(11): 3267-3281, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31019060

RESUMO

Matrix metalloproteinase (MMP)-8 and -9 released by degranulating polymorphonuclear cells (PMNs) promote pericellular proteolysis by binding to PMN surfaces in a catalytically active tissue inhibitor of metalloproteinases (TIMP)-resistant forms. The PMN receptor(s) to which MMP-8 and MMP-9 bind(s) is not known. Competitive binding experiments showed that Mmp-8 and Mmp-9 share binding sites on murine PMN surfaces. A novel form of TIMP-1 (an inhibitor of soluble MMPs) is rapidly expressed on PMN surfaces when human PMNs are activated. Membrane-bound TIMP-1 is the PMN receptor for pro- and active MMP-8 and -9 as shown by the following: 1) TIMP-1 is strikingly colocalized with MMP-8 and -9 on activated human PMN surfaces and in PMN extracellular traps; 2) minimal immunoreactive and active Mmp-8 or Mmp-9 are detected on the surface of activated Timp-1-/- murine PMNs; and 3) binding of exogenous Timp-1 (but not Timp-2) to Timp-1-/- murine PMNs reconstitutes the binding of exogenous pro-Mmp-8 and pro-Mmp-9 to the surface of Timp-1-/- PMNs. Unlike full-length pro-Mmp-8 and pro-Mmp-9, mutant pro-Mmp proteins lacking the COOH-terminal hemopexin domain fail to bind to Mmp-8-/-x Mmp-9-/- murine PMNs. Soluble hemopexin inhibits the binding of pro-Mmp-8 and pro-Mmp-9 to Mmp-8-/-x Mmp-9-/- murine PMNs. Thus, the COOH-terminal hemopexin domains of pro-Mmp-8 and pro-Mmp-9 are required for their binding to membrane-bound Timp-1 on murine PMNs. Exposing nonhuman primates to cigarette smoke upregulates colocalized expression of TIMP-1 with MMP-8 and MMP-9 on peripheral blood PMN surfaces. By anchoring MMP-8 and MMP-9 to PMN surfaces, membrane-bound TIMP-1 plays a counterintuitive role in promoting PMN pericellular proteolysis occurring in chronic obstructive pulmonary disease and other diseases.


Assuntos
Membrana Celular/metabolismo , Armadilhas Extracelulares/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neutrófilos/imunologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Células Cultivadas , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Domínios Proteicos/genética , Engenharia de Proteínas , Transporte Proteico , Proteólise , Inibidor Tecidual de Metaloproteinase-1/genética
8.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
9.
BMC Genomics ; 20(1): 22, 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626320

RESUMO

BACKGROUND: Aging is affected by genetic and environmental factors, and cigarette smoking is strongly associated with accumulation of senescent cells. In this study, we wanted to identify genes that may potentially be beneficial for cell survival in response to cigarette smoke and thereby may contribute to development of cellular senescence. RESULTS: Primary human bronchial epithelial cells from five healthy donors were cultured, treated with or without 1.5% cigarette smoke extract (CSE) for 24 h or were passaged into replicative senescence. Transcriptome changes were monitored using RNA-seq in CSE and non-CSE exposed cells and those passaged into replicative senescence. We found that, among 1534 genes differentially regulated during senescence and 599 after CSE exposure, 243 were altered in both conditions, representing strong enrichment. Pathways and gene sets overrepresented in both conditions belonged to cellular processes that regulate reactive oxygen species, proteasome degradation, and NF-κB signaling. CONCLUSIONS: Our results offer insights into gene expression responses during cellular aging and cigarette smoke exposure, and identify potential molecular pathways that are altered by cigarette smoke and may also promote airway epithelial cell senescence.


Assuntos
Brônquios/metabolismo , Senescência Celular/genética , Fumar Cigarros/genética , Brônquios/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fumar Cigarros/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , NF-kappa B/genética , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos
10.
Mol Cell Oncol ; 5(4): e1435182, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250907

RESUMO

Hyperplastic airway epithelial cells may be the cause for increased risk for lung cancer in patients with chronic lung diseases. The B-cell lymphoma 2 (Bcl-2) family member, Bcl-2-interacting killer (BIK), triggers cell death specifically in these hyperplastic cells because of adequate presence of Death-associated Protein Kinase 1 (DAPk1), BCL-2 Antagonist Killer (BAK), and Extracellular Signal-regulated Kinase 1/2 (ERK1/2). Therefore, BIK may be a useful tool to control the development of lung cancer in patients with chronic diseases.

11.
Clin Respir J ; 12(11): 2598-2605, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30257066

RESUMO

BACKGROUND: Current risk factors for Chronic Obstructive Pulmonary Disease mortality focus only on overall and respiratory death. We investigated whether risk factors for each specific cause of mortality are different depending on the outcome under consideration. METHODS: This retrospective cohort study included patients with a clinical diagnosis of COPD, older than 40, greater than 20 pack-years smoking history, and obstructive pattern on spirometry. Collected data included baseline spirometry, comorbidities, medication use, tobacco exposure, severe exacerbations, and cause-specific mortality. RESULTS: This 512 patient cohort of heavy smokers included 277 (54.1%) males, was on average 66.4 ± 9.4 years of age and primarily non-Hispanic white, 395 (83.2%). The average FEV1% was 52.1% (SD = 16.9%) and the median COTE score was 2 (IQR: 0-6). A total of 67 deaths were of respiratory causes in 26 patients (38.8%), malignancies in 21 (31.1%), cardiovascular causes in 6 (9%), and from other etiologies in 14 patients (20.1%). COTE index,low predicted FEV1%, and lower body mass index were significant predictors of overall mortality. Predictors of respiratory deaths were significantly impacted by lower FEV1%, history of COPD exacerbations, lower BMI, and higher number of pack-years smoked. Risk factors for all other cause-specific mortality combined included history of malignancy or cardiovascular disease and smoking status. CONCLUSION: Cause-specific mortality risk factors differ in patients with COPD.


Assuntos
Mortalidade/tendências , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Comorbidade , Progressão da Doença , Feminino , Volume Expiratório Forçado/fisiologia , Indicadores Básicos de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , New Mexico/epidemiologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Análise de Sobrevida
13.
Am J Respir Crit Care Med ; 198(10): 1254-1267, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29750543

RESUMO

RATIONALE: ADAM8 (a disintegrin and metalloproteinase domain-8) is expressed by leukocytes and epithelial cells in health, but its contribution to the pathogenesis of chronic obstructive pulmonary disease (COPD) is unknown. OBJECTIVES: To determine whether the expression of ADAM8 is increased in the lungs of patients with COPD and cigarette smoke (CS)-exposed mice, and whether ADAM8 promotes the development of COPD. METHODS: ADAM8 levels were measured in lung, sputum, plasma, and/or BAL fluid samples from patients with COPD, smokers, and nonsmokers, and wild-type (WT) mice exposed to CS versus air. COPD-like lung pathologies were compared in CS-exposed WT versus Adam8-/- mice. MEASUREMENTS AND MAIN RESULTS: ADAM8 immunostaining was reduced in macrophages, and alveolar and bronchial epithelial cells in the lungs of patients with COPD versus control subjects, and CS- versus air-exposed WT mice. ADAM8 levels were similar in plasma, sputum, and BAL fluid samples from patients with COPD and control subjects. CS-exposed Adam8-/- mice had greater airspace enlargement and airway mucus cell metaplasia than WT mice, but similar small airway fibrosis. CS-exposed Adam8-/- mice had higher lung macrophage counts, oxidative stress levels, and alveolar septal cell death rates, but lower alveolar septal cell proliferation rates and soluble epidermal growth factor receptor BAL fluid levels than WT mice. Adam8 deficiency increased lung inflammation by reducing CS-induced activation of the intrinsic apoptosis pathway in macrophages. Human ADAM8 proteolytically shed the epidermal growth factor receptor from bronchial epithelial cells to reduce mucin expression in vitro. Adam8 bone marrow chimera studies revealed that Adam8 deficiency in leukocytes and lung parenchymal cells contributed to the exaggerated COPD-like disease in Adam8-/- mice. CONCLUSIONS: Adam8 deficiency increases CS-induced lung inflammation, emphysema, and airway mucus cell metaplasia. Strategies that increase or prolong ADAM8's expression in the lung may have therapeutic efficacy in COPD.


Assuntos
Proteínas ADAM/genética , Antígenos CD/genética , Proteínas de Membrana/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Animais , Fumar Cigarros/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
14.
COPD ; 15(2): 206-213, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29697285

RESUMO

The binary approach to the diagnosis of Chronic Bronchitis (CB) is a major barrier to the study of the disease. We investigated whether severity of productive cough can be graded using symptoms and presence of fixed airflow obstruction (FAO), and whether the severity correlates with health status, exposures injurious to the lung, biomarkers of inflammation, and measures of airway wall thickening. Findings from a cross-sectional sample of 1,422 participants from the Lovelace Smokers Cohort (LSC) were validated in 4,488 participants from the COPDGene cohort (COPDGene). Health status was based on the St. George's Respiratory Questionnaire, and Medical Outcomes Study 36-Item Short Form Health Survey. Circulating CC16 levels were quantified by ELISA (LSC), and airway wall thickening was measured using computed tomography (COPDGene). FAO was defined as postbronchodilator FEV1/FVC <0.7. The presence and duration of productive cough and presence of FAO or wheeze were graded into Healthy Smokers, Productive Cough (PC), Chronic PC, PC with Signs of Airflow Obstruction, and Chronic PC with Signs of Airflow Obstruction. In both cohorts, higher grade of severity correlated with lower health status, greater frequency of injurious exposures, greater airway wall thickening, and lower circulating CC16 levels. Further, longitudinal follow-up suggested that disease resolution can occur at every grade of severity but is more common in groups of lower severity and least common once airway remodeling develops. Therefore, severity of productive cough can be graded based on symptoms and FAO and early intervention may benefit patients by changing the natural history of disease.


Assuntos
Remodelação das Vias Aéreas , Bronquite Crônica/fisiopatologia , Tosse/fisiopatologia , Nível de Saúde , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Adulto , Idoso , Bronquite Crônica/diagnóstico por imagem , Bronquite Crônica/epidemiologia , Bronquite Crônica/imunologia , Tosse/diagnóstico por imagem , Tosse/epidemiologia , Tosse/imunologia , Estudos Transversais , Exposição Ambiental/estatística & dados numéricos , Feminino , Volume Expiratório Forçado , Humanos , Modelos Logísticos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Índice de Gravidade de Doença , Fumar/epidemiologia , Tomografia Computadorizada por Raios X , Uteroglobina/imunologia , Capacidade Vital
15.
Am J Respir Cell Mol Biol ; 59(1): 13-17, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29522352

RESUMO

Chronic obstructive pulmonary disease (COPD) is a syndrome that comprises several lung pathologies, but subphenotyping the various disease subtypes has been difficult. One reason may be that current efforts focused on studying COPD once it has occurred do not allow tracing back to the different origins of disease. This perspective proposes that emphysema originates when susceptible airway, endothelial, and/or hematopoietic cells are exposed to environmental toxins such as cigarette smoke, biomass fuel, or traffic emissions. These susceptible cell types may initiate distinct pathobiological mechanisms ("COPD endotypes") that ultimately manifest the emphysematous destruction of the lung. On the basis of evidence from the "airway" endotype, we suggest that grading these endotypes by severity may allow better diagnosis of disease at early stages when intervention can be designed on the basis of the mechanisms involved. Therefore, genomic, proteomic, and metabolomic studies on at-risk patients will be important in the identification of biomarkers that help designate each endotype. Together with understanding of the involved molecular pathways that lead to disease manifestation, these efforts may lead to development of intervention strategies.


Assuntos
Doença Pulmonar Obstrutiva Crônica/diagnóstico , Remodelação das Vias Aéreas , Animais , Biomarcadores/metabolismo , Endofenótipos , Estudo de Associação Genômica Ampla , Humanos , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
16.
Eur Respir J ; 51(1)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29301918

RESUMO

Exposure to household air pollution (HAP) from solid fuel combustion affects almost half of the world population. Adverse respiratory outcomes such as respiratory infections, impaired lung growth and chronic obstructive pulmonary disease have been linked to HAP exposure. Solid fuel smoke is a heterogeneous mixture of various gases and particulates. Cell culture and animal studies with controlled exposure conditions and genetic homogeneity provide important insights into HAP mechanisms. Impaired bacterial phagocytosis in exposed human alveolar macrophages possibly mediates several HAP-related health effects. Lung pathological findings in HAP-exposed individuals demonstrate greater small airways fibrosis and less emphysema compared with cigarette smokers. Field studies using questionnaires, air pollution monitoring and/or biomarkers are needed to better establish human risks. Some, but not all, studies suggest that improving cookstove efficiency or venting emissions may be associated with reduced respiratory symptoms, lung function decline in women and severe pneumonia in children. Current studies focus on fuel switching, stove technology replacements or upgrades and air filter devices. Several governments have initiated major programmes to accelerate the upgrade from solid fuels to clean fuels, particularly liquid petroleum gas, which provides research opportunities for the respiratory health community.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar em Ambientes Fechados/efeitos adversos , Biomarcadores , Gases/toxicidade , Doenças Respiratórias/induzido quimicamente , Poluentes Atmosféricos/química , Animais , Culinária , Gases/química , Produtos Domésticos , Humanos , Exposição por Inalação/efeitos adversos , Macrófagos Alveolares/patologia , Doenças Respiratórias/fisiopatologia , Inquéritos e Questionários
17.
Sci Rep ; 8(1): 436, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29323189

RESUMO

Exposure to lipopolysaccharides (LPS) causes extensive neutrophilic inflammation in the airways followed by mucous cell hyperplasia (MCH) that is sustained by the anti-apoptotic protein, Bcl-2. To identify inflammatory factor(s) that are responsible for Bcl-2 expression, we established an organ culture system consisting of airway epithelial tissue from the rat nasal midseptum. The highest Muc5AC and Bcl-2 expression was observed when organ cultures were treated with brochoalveolar lavage (BAL) fluid harvested from rats 10 h post LPS instillation. Further, because BAL harvested from rats depleted of polymorphonuclear cells compared to controls showed increased Bcl-2 expression, analyses of cytokine levels in lavages identified IL-13 as an inducer of Bcl-2 expression. Ectopic IL-13 treatment of differentiated airway epithelial cells increased Bcl-2 and MUC5AC expression in the basal and apical regions of the cells, respectively. When Bcl-2 was blocked using shRNA or a small molecule inhibitor, ABT-263, mucous cell numbers were reduced due to increased apoptosis that disrupted the interaction of Bcl-2 with the pro-apoptotic protein, Bik. Furthermore, intranasal instillation of ABT-263 reduced the LPS-induced MCH in bik +/+ but not bik -/- mice, suggesting that Bik mediated apoptosis in hyperplastic mucous cells. Therefore, blocking Bcl-2 function could be useful in reducing IL-13 induced mucous hypersecretion.


Assuntos
Inflamação/metabolismo , Interleucina-13/metabolismo , Lipopolissacarídeos/efeitos adversos , Septo Nasal/citologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Apoptose , Líquido da Lavagem Broncoalveolar/imunologia , Hiperplasia , Masculino , Mucina-5AC/metabolismo , Septo Nasal/metabolismo , Septo Nasal/patologia , Técnicas de Cultura de Órgãos , Ratos
18.
Am J Respir Cell Mol Biol ; 58(6): 717-726, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29314865

RESUMO

Respiratory syncytial virus (RSV) is associated with enhanced progression of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. However, little is known about the role of IL-17 in RSV-induced lung injury. We first investigated the role of RSV infection in enhancing mucous cell hyperplasia (MCH) and airspace enlargement in the lungs of mice injured with elastase and LPS (E/LPS). Mice injured with E/LPS had an enhanced and prolonged neutrophilic response to RSV that was associated with decreased levels of type I IFN and increased levels of IL-17, IL-23, CXCL-1, granulocyte colony stimulating factor (GCSF), CXCL-5, and matrix metalloproteinase (MMP)-9. In addition, extent of MCH and mean weighted alveolar space were increased significantly in the lungs of E/LPS-injured mice infected with RSV compared with E/LPS-only or RSV-only controls. Interestingly, immunodepletion of IL-17 before viral infection diminished the RSV-driven MCH and airspace enlargement in the E/LPS-injured animals, suggesting that IL-17 may be a therapeutic target for MCH and airspace enlargement when enhanced by RSV infection.


Assuntos
Interleucina-17/metabolismo , Pneumonia Viral/fisiopatologia , Enfisema Pulmonar/virologia , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Hiperplasia/metabolismo , Hiperplasia/patologia , Interleucina-17/genética , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Elastase Pancreática/toxicidade , Pneumonia Viral/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/fisiopatologia , Infecções por Vírus Respiratório Sincicial/metabolismo
20.
Int J Chron Obstruct Pulmon Dis ; 12: 3171-3181, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29133979

RESUMO

Background: COPD is the third leading cause of death in the United States. Cigarette smoking accelerates the age-related forced expiratory volume in 1 s (FEV1) decline, an important determinant for the genesis of COPD. Hispanic smokers have lower COPD prevalence and FEV1 decline than non-Hispanic whites (NHWs). Patients and methods: A nutritional epidemiological study was conducted in the Lovelace Smokers cohort (LSC; n=1,829) and the Veterans Smokers cohort (n=508) to identify dietary nutrients (n=139) associated with average FEV1 and its decline and to assess whether nutrient intakes could explain ethnic disparity in FEV1 decline between Hispanics and NHW smokers. Results: Nutrients discovered and replicated to be significantly associated with better average FEV1 included magnesium, folate, niacin, vitamins A and D, eicosenoic fatty acid (20:1n9), eicosapentaenoic acid (20:5n3), docosapentaenoic acid (DPA; 22:5n3), docosahexaenoic acid (22:6n3), and fiber. In addition, greater intakes of eicosenoic fatty acid and DPA were associated with slower FEV1 decline in the LSC. Among omega 3 polyunsaturated fatty acids, DPA is the most potent nutrient associated with better average FEV1 and slower FEV1 decline. Adverse effect of continuous current smoking on FEV1 decline was completely negated in LSC members with high DPA intake (>20 mg/day). Slower FEV1 decline in Hispanics compared to NHWs may be due to the greater protection of eicosenoic fatty acid and DPA for FEV1 decline rather than greater intake of protective nutrients in this ethnic group. Conclusion: The protective nutrients for the preservation of FEV1 in ever smokers could lay foundation for designing individualized nutritional intervention targeting "optimal physiological levels" in human to improve lung function in ever smokers. Ethnic disparity in FEV1 decline may be explained by difference in magnitude of protection of dietary intakes of eicosenoic fatty acid and DPA between Hispanics and NHWs.


Assuntos
Fumar Cigarros/fisiopatologia , Dieta/etnologia , Ácido Eicosapentaenoico/administração & dosagem , Grupo com Ancestrais do Continente Europeu , Ácidos Graxos Insaturados/administração & dosagem , Hispano-Americanos , Pulmão/fisiopatologia , Estado Nutricional/etnologia , Fumantes , Adulto , Idoso , Fumar Cigarros/efeitos adversos , Fumar Cigarros/etnologia , Progressão da Doença , Feminino , Volume Expiratório Forçado , Disparidades nos Níveis de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , New Mexico/epidemiologia , Prevalência , Fatores de Proteção , Fatores de Risco
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