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1.
Eur Respir J ; 54(3)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31371443

RESUMO

Adhesion molecules may contribute to the development of interstitial lung disease (ILD) and have been proposed as prognostic biomarkers in idiopathic pulmonary fibrosis. Our objective was to determine whether the circulating adhesion molecules soluble intracellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and P-selectin are associated with subclinical ILD in community-dwelling adults.The Multi-Ethnic Study of Atherosclerosis enrolled males and females aged 45-84 years from six communities in the United States in 2000-2002. High attenuation areas were defined as the percentage of imaged lung volume with attenuation -600--250 HU on cardiac computed tomography (CT). Interstitial lung abnormalities were visually assessed on full-lung CT. Spirometry was performed on a subset of individuals. ILD hospitalisations and deaths were adjudicated.In fully adjusted analyses, higher levels of sICAM-1, sVCAM-1 and P-selectin were associated with greater high attenuation areas (2.94%, 95% CI 1.80-4.07%; 1.24%, 95% CI 0.14-2.35%; and 1.58%, 95% CI 0.92-2.23%, respectively), and greater rate of ILD hospitalisations (HR 1.36, 95% CI 1.03-1.80; 1.40, 95% CI 1.07-1.85; and 2.03, 95% CI 1.16-3.5, respectively). sICAM-1 was associated with greater prevalence of interstitial lung abnormalities (OR 1.39, 95% CI 1.13-1.71). sICAM-1 and P-selectin were associated with lower forced vital capacity (44 mL, 95% CI 12-76 mL and 29 mL, 95% CI 8-49 mL, respectively). sVCAM-1 and P-selectin were associated with increased risk of ILD death (HR 2.15, 95% CI 1.26-3.64 and 3.61, 95% CI 1.54-8.46, respectively).Higher levels of circulating sICAM-1, sVCAM-1 and P-selectin are independently associated with CT and spirometric measures of subclinical ILD, and increased rate of adjudicated ILD events among community-dwelling adults.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31339356

RESUMO

Rationale Interstitial lung abnormalities (ILA) are associated with the highest genetic risk locus for IPF; however, the extent to which there is additional overlap with IPF, or unique associations among those with ILA is not known. Objectives To perform a genome-wide association study (GWAS) of ILA. Methods: ILA and the subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES, COPDGene, Framingham Heart, ECLIPSE, MESA, and SPIROMICS studies. We performed a GWAS of ILA in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Measurements and Main Results Genome-wide genotyping data were available in 1,699 ILA cases and 10,274 controls. The MUC5B promoter variant rs35705950 was significantly associated with both ILA (p=2.6x10-27) and subpleural ILA (p=1.6x10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, p=3.8x10-8) and FCF1P3 (rs73199442, p=4.8x10-8) with ILA, and HTRE1 (rs7744971, p=4.2x10-8) with subpleural-predominant ILA. These novel associations were not associated with IPF. Of 12 previously reported IPF GWAS loci, 5 (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (p<0.05/12) with ILA. Conclusions In a GWAS of ILA in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common and suggest distinct genetically-driven biologic pathways between ILA and IPF.

4.
J Nutr ; 148(7): 1126-1134, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931068

RESUMO

Background: Activated vitamin D has anti-inflammatory properties. 25-Hydroxyvitamin D [25(OH)D] deficiency might contribute to subclinical interstitial lung disease (ILD). Objective: We examined associations between serum 25(OH)D concentrations and subclinical ILD among middle-aged to older adults who were free of cardiovascular disease at baseline. Methods: We studied 6302 Multi-Ethnic Study of Atherosclerosis (MESA) participants who had baseline serum 25(OH)D concentrations and computed tomography (CT) imaging spanning ≤ 10 y. Baseline cardiac CT scans (2000-2002) included partial lung fields. Some participants had follow-up cardiac CT scans at exams 2-5 and a full-lung CT scan at exam 5 (2010-2012), with a mean ± SD of 2.1 ± 1.0 scans. Subclinical ILD was defined quantitatively as high-attenuation areas (HAAs) between -600 and -250 Hounsfield units. We assessed associations of 25(OH)D with adjusted HAA volumes and HAA progression. We also examined associations between baseline 25(OH)D and the presence of interstitial lung abnormalities (ILAs) assessed qualitatively (yes or no) from full-lung CT scans at exam 5. Models were adjusted for sociodemographic characteristics, lifestyle factors (including smoking), and lung volumes. Results: The cohort's mean ± SD characteristics were 62.2 ± 10 y for age, 25.8 ± 10.9 ng/mL for 25(OH)D concentrations, and 28.3 ± 5.4 for body mass index (kg/m2); 53% were women, with 39% white, 27% black, 22% Hispanic, and 12% Chinese race/ethnicities. Thirty-three percent had replete (≥30 ng/mL), 35% intermediate (20 to <30 ng/mL), and 32% deficient (<20 ng/mL) 25(OH)D concentrations. Compared with those with replete concentrations, participants with 25(OH)D deficiency had greater adjusted HAA volume at baseline (2.7 cm3; 95% CI: 0.9, 4.5 cm3) and increased progression over a median of 4.3 y of follow-up (2.7 cm3; 95% CI: 0.9, 4.4 cm3) (P < 0.05). 25(OH)D deficiency was also associated with increased prevalence of ILAs 10 y later (OR: 1.5; 95% CI: 1.1, 2.2). Conclusions: Vitamin D deficiency is independently associated with subclinical ILD and its progression, based on both increased HAAs and ILAs, in a community-based population. Further studies are needed to examine whether vitamin D repletion can prevent ILD or slow its progression. The MESA cohort design is registered at www.clinicaltrials.gov as NCT00005487.

5.
Respir Med ; 140: 108-114, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29957270

RESUMO

BACKGROUND: Lung fibrosis is attributed to derangements in extracellular matrix remodeling, a process driven by collagen turnover. We examined the association of two collagen biomarkers, carboxy-terminal telopeptide of collagen type I (ICTP) and amino-terminal propeptide of type III procollagen (PIIINP), with subclinical interstitial lung disease (ILD) in adults. METHODS: We performed a cross-sectional analysis of 3244 participants age 45-84 years in the Multi-Ethnic Study of Atherosclerosis. Serum ICTP and PIIINP levels were measured at baseline by radioimmunoassay. Subclinical ILD was defined as high attenuation areas (HAA) in the lung fields on baseline cardiac CT scans. Interstitial lung abnormalities (ILA) were measured in 1082 full-lung CT scans at 9.5 years median follow-up. We used generalized linear models to examine the associations of collagen biomarkers with HAA and ILA. RESULTS: Median (IQR) for ICTP was 3.2 µg/L (2.6-3.9 µg/L) and for PIIINP was 5.3 µg/L (4.5-6.2 µg/L). In fully adjusted models, each SD increment in ICTP was associated with a 1.3% increment in HAA (95% CI 0.2-2.4%, p = 0.02) and each SD increment in PIIINP was associated with a 0.96% increment in HAA (95% CI 0.06-1.9%, p = 0.04). There was no association between ICTP or PIIINP and ILA. There was no evidence of effect modification by gender, race, smoking status or eGFR. CONCLUSIONS: Higher levels of collagen biomarkers are associated with greater HAA independent of gender, race and smoking status. This suggests that extracellular matrix remodeling may accompany subclinical ILD prior to the onset of clinically evident disease.

6.
Respir Med ; 131: 70-76, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28947046

RESUMO

BACKGROUND: Frail lung transplant candidates are more likely to be delisted or die without receiving a transplant. Further knowledge of what frailty represents in this population will assist in developing interventions to prevent frailty from developing. We set out to determine whether frail lung transplant candidates have reduced exercise capacity independent of disease severity and diagnosis. METHODS: Sixty-eight adult lung transplant candidates underwent cardiopulmonary exercise testing (CPET) and a frailty assessment (Fried's Frailty Phenotype (FFP)). Primary outcomes were peak workload and peak aerobic capacity (V˙O2). We used linear regression to adjust for age, gender, diagnosis, and lung allocation score (LAS). RESULTS: The mean ± SD age was 57 ± 11 years, 51% were women, 57% had interstitial lung disease, 32% had chronic obstructive pulmonary disease, 11% had cystic fibrosis, and the mean LAS was 40.2 (range 19.2-94.5). In adjusted models, peak workload decreased by 10 W (95% CI 4.7 to 14.6) and peak V˙O2 decreased by 1.8 mL/kg/min (95% CI 0.6 to 2.9) per 1 unit increment in FFP score. After adjustment, exercise tolerance was 38 W lower (95% CI 18.4 to 58.1) and peak V˙O2 was 8.5 mL/kg/min lower (95% CI 3.3 to 13.7) among frail participants compared to non-frail participants. Frailty accounted for 16% of the variance (R2) of watts and 19% of the variance of V˙O2 in adjusted models. CONCLUSION: Frailty contributes to reduced exercise capacity among lung transplant candidates independent of disease severity.


Assuntos
Fibrose Cística/fisiopatologia , Tolerância ao Exercício , Fragilidade/fisiopatologia , Doenças Pulmonares Intersticiais/fisiopatologia , Transplante de Pulmão , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Adulto , Idoso , Fibrose Cística/complicações , Fibrose Cística/cirurgia , Teste de Esforço , Feminino , Fragilidade/etiologia , Humanos , Modelos Lineares , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/cirurgia , Masculino , Pessoa de Meia-Idade , Força Muscular , Consumo de Oxigênio , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/cirurgia
7.
Am J Respir Crit Care Med ; 196(8): 1031-1039, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28753039

RESUMO

RATIONALE: The impact of a broad range of occupational exposures on subclinical interstitial lung disease (ILD) has not been studied. OBJECTIVES: To determine whether occupational exposures to vapors, gas, dust, and fumes (VGDF) are associated with high-attenuation areas (HAA) and interstitial lung abnormalities (ILA), which are quantitative and qualitative computed tomography (CT)-based measurements of subclinical ILD, respectively. METHODS: We performed analyses of participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis), a population-based cohort aged 45-84 years at recruitment. HAA was measured at baseline and on serial cardiac CT scans in 5,702 participants. ILA was ascertained in a subset of 2,312 participants who underwent full-lung CT scanning at 10-year follow-up. Occupational exposures were assessed by self-reported VGDF exposure and by job-exposure matrix (JEM). Linear mixed models and logistic regression were used to determine whether occupational exposures were associated with log-transformed HAA and ILA. Models were adjusted for age, sex, race/ethnicity, education, employment status, tobacco use, and scanner technology. MEASUREMENTS AND MAIN RESULTS: Each JEM score increment in VGDF exposure was associated with 2.64% greater HAA (95% confidence interval [CI], 1.23-4.19%). Self-reported vapors/gas exposure was associated with an increased odds of ILA among those currently employed (1.76-fold; 95% CI, 1.09-2.84) and those less than 65 years old (1.97-fold; 95% CI, 1.16-3.35). There was no consistent evidence that occupational exposures were associated with progression of HAA over the follow-up period. CONCLUSIONS: JEM-assigned and self-reported exposures to VGDF were associated with measurements of subclinical ILD in community-dwelling adults.


Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/etiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Grupos Étnicos , Feminino , Humanos , Modelos Logísticos , Doenças Pulmonares Intersticiais/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados Unidos
8.
Am J Respir Crit Care Med ; 196(10): 1311-1317, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28570100

RESUMO

RATIONALE: Matrix metalloproteinase-7 (MMP-7) has been implicated in interstitial lung disease pathobiology and proposed as a diagnostic and prognostic biomarker of idiopathic pulmonary fibrosis. OBJECTIVES: To test associations between serum MMP-7 and lung function, respiratory symptoms, interstitial lung abnormalities (ILA), and all-cause mortality in community-dwelling adults sampled without regard to respiratory symptoms or disease. METHODS: We measured serum MMP-7 in 1,227 participants in MESA (Multi-Ethnic Study of Atherosclerosis) at baseline. The 5-year outcome data were available for spirometry (n = 697), cough (n = 722), and dyspnea (n = 1,050). The 10-year outcome data were available for ILA (n = 561) and mortality (n = 1,227). We used linear, logistic, and Cox regression to control for potential confounders. MEASUREMENTS AND MAIN RESULTS: The mean (±SD) serum MMP-7 level was 4.3 (±2.5) ng/ml (range, 1.2-24.1 ng/ml). In adjusted models, each natural log unit increment in serum MMP-7 was associated with a 3.7% absolute decrement in FVC% (95% confidence interval [CI] = 0.9-6.6%), a 1.6-fold increased odds of exertional dyspnea (95% CI = 1.3-1.9), a 1.5-fold increased odds of ILAs (95% CI = 1.1-2.1), and a 2.2-fold increased all-cause mortality rate (95% CI = 1.9-2.5). The associations with ILA and mortality tended to be stronger among never-smokers (P values for interaction 0.06 and 0.01, respectively). CONCLUSIONS: Serum MMP-7 levels may be a quantitative biomarker of subclinical extracellular matrix remodeling in the lungs of community-dwelling adults, which may facilitate investigation of subclinical interstitial lung disease.


Assuntos
Doenças Assintomáticas/mortalidade , Grupos Étnicos/estatística & dados numéricos , Vida Independente/estatística & dados numéricos , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/fisiopatologia , Metaloproteinase 7 da Matriz/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
Am J Respir Crit Care Med ; 196(11): 1434-1442, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28613921

RESUMO

RATIONALE: Areas of increased lung attenuation visualized by computed tomography are associated with all-cause mortality in the general population. It is uncertain whether this association is attributable to interstitial lung disease (ILD). OBJECTIVES: To determine whether high-attenuation areas are associated with the risk of ILD hospitalization and mortality in the general population. METHODS: We performed a cohort study of 6,808 adults aged 45-84 years sampled from six communities in the United States. High-attenuation areas were defined as the percentage of imaged lung volume with attenuation values between -600 and -250 Hounsfield units. An adjudication panel determined ILD hospitalization and death. MEASUREMENTS AND MAIN RESULTS: After adjudication, 52 participants had a diagnosis of ILD during 75,232 person-years (median, 12.2 yr) of follow-up. There were 48 hospitalizations attributable to ILD (crude rate, 6.4 per 10,000 person-years). Twenty participants died as a result of ILD (crude rate, 2.7 per 10,000 person-years). High-attenuation areas were associated with an increased rate of ILD hospitalization (adjusted hazard ratio, 2.6 per 1-SD increment in high-attenuation areas; 95% confidence interval, 1.9-3.5; P < 0.001), a finding that was stronger among men, African Americans, and Hispanics. High-attenuation areas were also associated with an increased rate of ILD-specific death (adjusted hazard ratio, 2.3; 95% confidence interval, 1.7-3.0; P < 0.001). Our findings were consistent among both smokers and nonsmokers. CONCLUSIONS: Areas of increased lung attenuation are a novel risk factor for ILD hospitalization and mortality. Measurement of high-attenuation areas by screening and diagnostic computed tomography may be warranted in at-risk adults.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade
10.
Ann Am Thorac Soc ; 14(12): 1786-1795, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28613935

RESUMO

RATIONALE: Obstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis by promoting alveolar epithelial injury via tractional forces and intermittent hypoxia. OBJECTIVES: To determine whether OSA is associated with subclinical interstitial lung disease (ILD) and with biomarkers of alveolar epithelial injury and remodeling. METHODS: We performed cross-sectional analyses of 1,690 community-dwelling adults who underwent 15-channel in-home polysomnography and thoracic computed tomographic imaging in the Multi-Ethnic Study of Atherosclerosis. We measured the obstructive apnea-hypopnea index (oAHI) by polysomnography and high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) by computed tomography. Serum matrix metalloproteinase-7 (MMP-7) and surfactant protein-A (SP-A) were measured by ELISA in 99 participants. We used generalized linear models to adjust for potential confounders. RESULTS: The mean age was 68 years, and the mean forced vital capacity was 97% predicted. The median oAHI was 8.4 events/h, and 32% had an oAHI greater than 15. After adjusting for demographics, smoking, and center, an oAHI greater than 15 was associated with a 4.0% HAA increment (95% confidence interval [CI], 1.4-6.8%; P = 0.003) and 35% increased odds of ILA (95% CI, 13-61%; P = 0.001). However, there was evidence that these associations varied by body mass index (BMI) (P for interaction = 0.08 and 0.04, respectively). Among those with a BMI less than 25 kg/m2, an oAHI greater than 15 was associated with a 6.1% HAA increment (95% CI, 0.5-12%; P = 0.03) and 2.3-fold increased odds of ILA (95% CI, 1.3-4.1; P = 0.005). Among those with a BMI greater than 30 kg/m2, an oAHI greater than 15 was associated with 1.8-fold greater odds of ILA (95% CI, 1.1-2.9; P = 0.01) but was not associated with HAA. There were no meaningful associations detected among those with a BMI of 25-30 kg/m2. Greater oAHI was associated higher serum SP-A and MMP-7 levels, particularly among those with a BMI less than 25 kg/m2. CONCLUSIONS: Moderate to severe OSA is associated with subclinical ILD and with evidence of alveolar epithelial injury and extracellular matrix remodeling in community-dwelling adults, an association that is strongest among normal-weight individuals. These findings support the hypothesis that OSA might contribute to early ILD.


Assuntos
Biomarcadores/sangue , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/epidemiologia , Apneia Obstrutiva do Sono/complicações , Idoso , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Modelos Lineares , Masculino , Metaloproteinase 7 da Matriz/sangue , Pessoa de Meia-Idade , Polissonografia , Estudos Prospectivos , Proteína A Associada a Surfactante Pulmonar/sangue , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologia
12.
Thorax ; 72(5): 472-474, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28130491

RESUMO

We investigated associations of plasma lipoproteins with subclinical interstitial lung disease (ILD) by measuring high attenuation areas (HAA: lung voxels between -600 and -250 Hounsfield units) in 6700 adults and serum MMP-7 and SP-A in 1216 adults age 45-84 without clinical cardiovascular disease in Multi-Ethnic Study of Atherosclerosis. In cross-sectional analyses, each SD decrement in high density lipoprotein cholesterol (HDL-C) was associated with a 2.12% HAA increment (95% CI 1.44% to 2.79%), a 3.53% MMP-7 increment (95% CI 0.93% to 6.07%) and a 6.37% SP-A increment (95% CI 1.35% to 11.13%), independent of demographics, smoking and inflammatory biomarkers. These findings support a novel hypothesis that HDL-C might influence subclinical lung injury and extracellular matrix remodelling.


Assuntos
Lipoproteínas/sangue , Doenças Pulmonares Intersticiais/sangue , Proteína A Associada a Surfactante Pulmonar/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Masculino , Metaloproteinase 7 da Matriz/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia Computadorizada por Raios X
13.
Eur Respir J ; 48(5): 1442-1452, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27471206

RESUMO

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking.We measured high attenuation areas (HAA; percentage of lung voxels between -600 and -250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis.HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3-11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8-13.0), lower forced vital capacity (FVC) (mean adjusted difference -82 mL, 95% CI -119--44), lower 6-min walk distance (mean adjusted difference -40 m, 95% CI -1--80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43-2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39-1.79).High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults.


Assuntos
Pulmão/diagnóstico por imagem , Radiografia Torácica , Tomografia Computadorizada por Raios X , Adulto , Idoso , Biomarcadores/sangue , Proteína C-Reativa/análise , Exercício , Matriz Extracelular/metabolismo , Feminino , Fibrose , Humanos , Inflamação , Interleucina-6/sangue , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Masculino , Metaloproteinase 7 da Matriz/sangue , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fumar , Espirometria/métodos
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