Systemic inflammation in young adults is associated with abnormal lung function in middle age.
ABSTRACT: BACKGROUND:Systemic inflammation is associated with reduced lung function in both healthy individuals and those with chronic obstructive pulmonary disease (COPD). Whether systemic inflammation in healthy young adults is associated with future impairment in lung health is uncertain. METHODOLOGY/PRINCIPAL FINDINGS:We evaluated the association between plasma fibrinogen and C-reactive protein (CRP) in young adults and lung function in the Coronary Artery Risk Development in Young Adults cohort study. Higher year 7 fibrinogen was associated with greater loss of forced vital capacity (FVC) between years 5 and 20 (439 mL in quartile 4 vs. 398 mL in quartile 1, P<0.001) and forced expiratory volume in 1 second (FEV(1)) (487 mL in quartile 4 vs. 446 mL in quartile 1, P<0.001) independent of cigarette smoking, body habitus, baseline lung function and demographic factors. Higher year 7 CRP was also associated with both greater loss of FVC (455 mL in quartile 4 vs. 390 mL in quartile 1, P<0.001) and FEV(1) (491 mL in quartile 4 vs. 442 mL in quartile 1, P = 0.001). Higher year 7 fibrinogen and CRP were associated with abnormal FVC at year 20 (odds ratio (OR) per standard deviation 1.51 (95% confidence interval (CI): 1.30-1.75) for fibrinogen and 1.35 (95% CI: 1.14-1.59) for CRP). Higher year 5 fibrinogen was additionally associated with abnormal FEV(1). A positive interaction was observed between pack-years cigarette smoking and year 7 CRP for the COPD endpoint, and among participants with greater than 10 pack-years of cigarette exposure, year 7 CRP was associated with greater odds of COPD at year 20 (OR per standard deviation 1.53 (95% CI: 1.08-2.16). CONCLUSION/SIGNIFICANCE:Systemic inflammation in young adults is associated with abnormal lung function in middle age. In particular, elevated CRP may identify vulnerability to COPD among individuals who smoke. TRIAL REGISTRATION:ClinicalTrials.gov NCT00005130.
Project description:<h4>Background</h4>Systemic inflammation has been associated with reduced lung function. Adhesion molecules, such as intercellular adhesion molecule (ICAM)-1 and P-selectin, figure importantly in initiating the inflammatory response. We studied the association between ICAM-1 and P-selectin concentrations and lung function in the Coronary Artery Risk Development in Young Adults study.<h4>Methods</h4>Spirometry testing was conducted at years 5, 10, and 20. ICAM-1 and P-selectin were assayed at year 15.<h4>Results</h4>Complete data were obtained from 2,455 participants. We first predicted year-20 lung function from year-15 ICAM-1 concentration data. After controlling for race, gender, height, age, physical activity, smoking status, alcohol intake, BMI, and asthma status, all taken at year 15, the year-20 FVC was 164 mL higher (p < 0.0001) and FEV(1) was 164 mL higher (p = 0.0003) in the lowest ICAM-1 concentration quartile than the highest ICAM-1 quartile, whereas the FEV(1)/FVC ratio showed no association (p = 0.25). We then predicted the year-15 ICAM-1 concentration from year-5 lung function and change in lung function (year 10 - year 5). The year-15 ICAM-1 concentration was about 13 ng/mL higher in the lowest vs highest quartile of either the year-5 FVC (p = 0.01) or year-5 FEV(1) (p = 0.005). Year-15 ICAM-1 concentration was unrelated to year-5 FEV(1)/FVC ratio. Greater loss in FVC and FEV(1) (year 10 - year 5) also was associated with higher year-15 ICAM-1 concentrations. Associations between P-selectin and lung function followed a similar but weaker pattern to that observed for ICAM-1.<h4>Conclusions</h4>These data suggest a bidirectional association between circulating adhesion molecules, such as ICAM-1 and P-selectin, and pattern of lung function change in adults.
Project description:<h4>Objectives</h4>Vitamin D deficiency is associated with chronic obstructive pulmonary disease (COPD). We examined the cross-sectional association between 25-hydroxyvitamin D (25(OH)D) and lung function impairment and assessed whether vitamin D deficiency is related to long-term mortality in those with impaired lung function.<h4>Design</h4>Prospective study SETTING: General practices in the UK.<h4>Participants</h4>3575 men aged 60-79 years with no prevalent heart failure.<h4>Outcome measures</h4>Airway obstruction and mortality. The Global Initiative on Obstructive Lung diseases (GOLD) spirometry criteria was used to define airway obstruction.<h4>Results</h4>During the follow-up period of 20 years, there were 2327 deaths (114 COPD deaths). Vitamin D deficiency was defined as serum 25(OH)D levels<10 ng/mL; insufficiency as 25(OH)D 10-19 ng/mL; sufficient as 25(OH)D>20 ng/mL. In cross-sectional analysis, vitamin D deficiency was more prevalent in those with moderate COPD (FEV/FVC <70% and FEV<sub>1</sub> 50 to <80%; FEV<sub>1</sub>, forced expiratory volume in 1 s and FVC, forced vital capacity) and severe COPD (FEV/FVC <70% and FEV<sub>1</sub> <50%) but not in those with mild COPD (FEV/FVC <70% and FEV<sub>1</sub> <u>></u>80%) or restrictive lung disease (FEV<sub>1</sub>/FVC <u>></u>70% and FVC <80%) compared with men with normal lung function . Vitamin D deficiency was associated with increased risk of total and respiratory mortality in both men with COPD and men with restrictive lung disease after adjustment for confounders and inflammation. The adjusted HRs (95% CI) for total mortality comparing levels of 25(OH)D<10 ng/mL to 25(OH)D>=20 ng/mL were 1.39 (1.10 to 1.75), 1.52 (1.17 to 1.98), 1.58 (1.17 to 2.14) and 1.39 (0.83 to 2.33) for those with no lung impairment, restrictive lung function, mild/moderate COPD and severe COPD, respectively.<h4>Conclusion</h4>Men with COPD were more likely to be vitamin D deficient than those with normal lung function. Vitamin D deficiency is associated with increased all-cause mortality in older men with no lung impairment as well as in those with restrictive or obstructive lung impairment.
Project description:Activation of toll-like receptors (TLR1, TLR5, TLR6) and downstream markers (CCR1, MAPK14, ICAM1) leads to increased systemic inflammation. Our objective was to study the association between the gene expression levels of these six genes and lung function (Forced Expiratory Volume in one second (FEV<sub>1</sub>), Forced Vital Capacity (FVC) and FEV<sub>1</sub>/FVC). We studied gene expression levels and lung function in the Coronary Artery Risk Development in Young Adults study. Spirometry testing was used to measure lung function and gene expression levels were measured using the Nanostring platform. Multivariate linear regression models were used to study the association between lung function measured at year 30, 10-year decline from year 20 to year 30, and gene expression levels (highest quartile divided into two levels - 75th to 95th and>95th to 100th percentile) adjusting for center, smoking and BMI, measured at year 25. Year 30 FEV<sub>1</sub> and FVC were lower in the highest level of TLR5 compared to the lowest quartile with difference of 4.00% (p for trend: 0.04) and 3.90% (p for trend: 0.05), respectively. The 10-year decline of FEV<sub>1</sub> was faster in the highest level of CCR1 as compared to the lowest quartile with a difference of 1.69% (p for trend: 0.01). There was no association between gene expression and FEV<sub>1</sub>/FVC. Higher gene expression levels in TLR5 and CCR1 are associated with lower lung function and faster decline in FEV<sub>1</sub> over 10 years, in a threshold manner, providing new insights into the role of inflammation in lung function.
Project description:The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-? and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV(1), FEV(1)/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV(1) related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-?) formed another cluster associated with both DLCO and FEV(1) related parameters. Associations of Fibrinogen with DLCO and MPO with FEV(1)/FVC were stronger in patients without metabolic syndrome (r ?=? -0.52, p ?=? 0.005 and r ?=? -0.61, p =? 0.023, respectively) compared to patients with coexisting metabolic syndrome (r ?=? -0.25, p ?= ?0.47 and r ?=? -0.15, p ?= ?0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV(1), FEV(1)/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD.
Project description:<h4>Background</h4>Circulating markers of oxidative stress have been associated with lower lung function. Our objective was to study the association of gene expression levels of oxidative stress pathway genes (ALOX12, ALOX15, ARG2, GSTT1, LPO, MPO, NDUFB3, PLA2G7, and SOD3) and lung function forced expiratory volume in one second (FEV<sub>1</sub> ), forced vital capacity (FVC) in Coronary Artery Risk Development in Young Adults study.<h4>Methods</h4>Lung function was measured using spirometry and the Nanostring platform was used to estimate gene expression levels. Linear regression models were used to study association of lung function measured at year 30, 10-year decline in lung function and gene expression after adjustment for center, smoking, and BMI, measured at year 25.<h4>Results</h4>The 10-year decline of FEV<sub>1</sub> was faster in highest NDUFB3 quartile compared to the lowest (difference = -2.09%; p = 0.001) after adjustment for multiple comparisons. The 10-year decline in FEV<sub>1</sub> and FVC was nominally slower in highest versus lowest quartile of PLA2G7 (difference = 1.14%; p = 0.02, and difference = 1.06%; p = 0.005, respectively). The other genes in the study were not associated with FEV<sub>1</sub> or FVC.<h4>Conclusion</h4>Higher gene expression levels in oxidative stress pathway genes are associated with faster 10-year FEV<sub>1</sub> decline.
Project description:Recent data suggest beneficial effects of fiber intake on chronic respiratory symptoms in adults that are independent of antioxidant vitamin intake, but little is known about fiber consumption in relation to lung function and chronic obstructive pulmonary disease (COPD). The authors investigated the association of fiber intake with lung function and COPD in 11,897 US men and women from the Atherosclerosis Risk in Communities study (1987-1989). After control for potential confounders, positive associations were found between lung function and fiber intake from all sources as well as from cereal or fruit alone. Compared with those in the lowest quintile, participants in the highest quintile of total fiber intake had a 60.2-ml higher forced expiratory volume in 1 second (FEV(1)) (p for trend < 0.001), 55.2-ml higher forced vital capacity (FVC) (p = 0.001), 0.4% higher FEV(1)/FVC ratio (p = 0.040), 1.8% higher percent predicted FEV(1) (p < 0.001), and 1.4% higher percent predicted FVC (p = 0.001). Adjusted odds ratios of COPD for the highest versus lowest quintiles of intake were 0.85 (p = 0.044) for total fiber, 0.83 (p = 0.021) for cereal fiber, and 0.72 (p = 0.005) for fruit fiber. This study provides the first known evidence that dietary fiber is independently associated with better lung function and reduced prevalence of COPD.
Project description:<i>Background and Objectives:</i> We studied whether the extent of exertional oxygen desaturation and emphysema could cause greater mortality in COPD and asthma independent of airflow obstruction. <i>Materials and Methods:</i> We performed a 5-year longitudinal observational study in COPD and asthma patients who matched for airflow obstruction severity. All subjects performed a 6-min walk test (6MWT) and high-resolution computed tomography (HRCT) and followed spirometry and oxygen saturation (SpO<sub>2</sub>) during the 6MWT every 3-6 months. Overall survival was recorded. Cumulative survival curves were performed according to the Kaplan-Meier method and compared with the log-rank test. <i>Results:</i> The COPD group had higher emphysema scores, higher Δinspiratory capacities (ICs) and lower SpO<sub>2</sub> during the 6MWT, which showed a greater yearly decline in FEV<sub>1</sub> (40.6 mL) and forced vital capacity (FVC) (28 mL) than the asthma group (FEV<sub>1</sub>, 9.6 mL; FVC, 1.2 mL; <i>p</i> < 0.05). The emphysema-predominant COPD group had an accelerated annual decline in lung function and worse survival. The nadir SpO<sub>2</sub> ≤ 80% and a higher emphysema score were the strong risk factors for mortality in COPD patients. <i>Conclusions:</i> The greater structural changes with a higher emphysema score and greater desaturation during the 6MWT in COPD may contribute to worse yearly decline in FEV<sub>1</sub> and higher five-year mortality than in asthma patients with a similar airflow obstruction. The lowest SpO<sub>2</sub> ≤ 80% during the 6MWT and emphysema-predominant COPD were the strong independent factors for mortality in chronic obstructive airway disease patients.
Project description:<h4>Background</h4>To explore the correlations between SAA, CRP, and clinical indices of patients with acutely exacerbated chronic obstructive pulmonary disease (AECOPD).<h4>Methods</h4>A total of 120 patients with AECOPD and another 120 with remitted COPD were enrolled in an AECOPD group and a COPD remission group, respectively. Meanwhile, 120 healthy subjects were included as a control group. SAA, CRP, PCT, Fbg, IL-8, IL-6, TNF-?, and IP-10 levels were detected. FEV<sub>1</sub> and FEV<sub>1</sub> /FVC were measured.<h4>Results</h4>Compared with control group, the serum levels of SAA, CRP, PCT, Fbg, IL-8, IL-6, TNF-?, and IP-10 significantly increased in COPD remission group (P < 0.05). The levels of AECOPD group significantly exceeded those of COPD remission group (P < 0.05). The levels of AECOPD patients with different GOLD grades were significantly different (P < 0.05). AECOPD group had significantly lower FEV<sub>1</sub> and FEV<sub>1</sub> /FVC than those of COPD remission group (P < 0.05). The CAT score of AECOPD patients was (18.41 ± 2.55) points. The levels of SAA, CRP, PCT, Fbg, IL-8, IL-6, TNF-?, and IP-10 were negatively correlated with FEV<sub>1</sub> and FEV<sub>1</sub> /FVC, and positively correlated with CAT score. The area under receiver operating characteristic curve of SAA was largest (0.931). The cutoff values for SAA, CRP, PCT and Fbg were 18.68 mg/L, 14.70 mg/L, 0.39 ?g/L, 3.91 g/L, 0.46 ?g/L, 24.17 ?g/L, 7.18 mg/L, and 83.19 ng/L, respectively.<h4>Conclusions</h4>Serum levels of SAA, CRP, PCT, Fbg, IL-8, IL-6, TNF-?, and IP-10 in AECOPD patients were elevated, which may undermine pulmonary functions. SAA can be used as an effective index for AECOPD diagnosis and treatment.
Project description:<h4>Objectives</h4>Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cerebrovascular disease, which might be associated with decreases in cerebral blood flow. Since studies examining cerebral blood flow in COPD remain scarce and are limited by sample size, we aimed to study cerebral blood flow in participants with and without COPD.<h4>Design</h4>Observational cohort study.<h4>Setting</h4>Population-based Rotterdam Study.<h4>Participants</h4>4177 participants (age 68.0±8.5 years; 53% females) with and without COPD.<h4>Predictor variable</h4>Spirometry and pulmonary diffusing capacity.<h4>Outcome measures</h4>Cerebral blood flow by two-dimensional phase-contrast cerebral MRI.<h4>Results</h4>Compared with subjects with normal spirometry (forced expiratory volume in 1 s (FEV<sub>1</sub>)/forced vital capacity (FVC) ≥0.7 and FEV<sub>1</sub> ≥80%), multivariable adjusted cerebral blood flow (mL/min) was preserved in subjects with COPD Global initiative for Chronic Obstructive Lung Disease (GOLD1) (FEV<sub>1</sub>/FVC <0.7 and FEV<sub>1</sub> ≥80%), but significantly lower in subjects with COPD GOLD2-3 (FEV<sub>1</sub>/FVC <0.7 and FEV<sub>1</sub> <80%), even after adjustment for cardiovascular comorbidities. In sex-stratified analyses, this difference in cerebral blood flow was statistically significant in women but not in men. Cerebral blood flow was lowest in subjects with FEV<sub>1</sub>, FVC and diffusion lung capacity for carbon monoxide % predicted values in the lowest quintile, even after adjustment for cardiovascular comorbidities and cardiac function.<h4>Conclusion</h4>We observed a lowered cerebral blood flow in subjects with COPD GOLD2-3.
Project description:One quarter of individuals with Preserved Ratio Impaired Spirometry (PRISm) will develop airflow obstruction, but there are no established methods to identify these individuals. We examined the utility of FVC/TLC in identifying features of obstructive lung disease. The ratio of post-bronchodilator FVC and TLC<sub>CT</sub> from chest CT (FVC/TLC<sub>CT</sub>) among current and former smokers with PRISm (FEV<sub>1</sub>/FVC ≥ 0.7 and FEV1 < 80%) in COPDGene was used to stratify subjects into quartiles: very high, high, low, and very low. We examined the associations between FVC/TLC<sub>CT</sub> quartiles and (1) baseline characteristics, (2) respiratory exacerbations, (3) progression to COPD at 5 years, and (4) all-cause mortality. Among participants with PRISm at baseline (n = 1,131), the very low FVC/TLC<sub>CT</sub> quartile was associated with increased gas trapping and emphysema, and higher rates of progression to COPD at 5 years (36% versus 17%; p < 0.001) relative to the very high quartile. The very low FVC/TLC<sub>CT</sub> quartile was associated with increased total (IRR = 1.65; 95% CI [1.07-2.54]) and severe (IRR = 2.24; 95% CI [1.29-3.89]) respiratory exacerbations. Mortality was lower in the very high FVC/TLC<sub>CT</sub> quartile relative to the other quartiles combined. Reduced FVC/TLC<sub>CT</sub> ratio in PRISm is associated with increased symptoms, radiographic emphysema and gas trapping, exacerbations, and progression to COPD.