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1.  Fibrotic extracellular matrix activates a profibrotic positive feedback loop 
The Journal of Clinical Investigation  2014;124(4):1622-1635.
Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment.
doi:10.1172/JCI71386
PMCID: PMC3971953  PMID: 24590289
3.  Smoking Characteristics and Comorbidities in the Power To Quit Randomized Clinical Trial for Homeless Smokers 
Nicotine & Tobacco Research  2012;15(1):22-28.
Introduction:
Smoking prevalence in homeless populations is strikingly high (∼70%); yet, little is known about effective smoking cessation interventions for this population. We conducted a community-based clinical trial, Power To Quit (PTQ), to assess the effects of motivational interviewing (MI) and nicotine patch (nicotine replacement therapy [NRT]) on smoking cessation among homeless smokers. This paper describes the smoking characteristics and comorbidities of smokers in the study.
Methods:
Four hundred and thirty homeless adult smokers were randomized to either the intervention arm (NRT + MI) or the control arm (NRT + Brief Advice). Baseline assessment included demographic information, shelter status, smoking history, motivation to quit smoking, alcohol/other substance abuse, and psychiatric comorbidities.
Results:
Of the 849 individuals who completed the eligibility survey, 578 (68.1%) were eligible and 430 (74.4% of eligibles) were enrolled. Participants were predominantly Black, male, and had mean age of 44.4 years (S D = 9.9), and the majority were unemployed (90.5%). Most participants reported sleeping in emergency shelters; nearly half had been homeless for more than a year. Nearly all the participants were daily smokers who smoked an average of 20 cigarettes/day. Nearly 40% had patient health questionnaire-9 depression scores in the moderate or worse range, and more than 80% screened positive for lifetime history of drug abuse or dependence.
Conclusions:
This study demonstrates the feasibility of enrolling a diverse sample of homeless smokers into a smoking cessation clinical trial. The uniqueness of the study sample enables investigators to examine the influence of nicotine dependence as well as psychiatric and substance abuse comorbidities on smoking cessation outcomes.
doi:10.1093/ntr/nts030
PMCID: PMC3611988  PMID: 22589422
4.  Randomized Trial of Zileuton for Treatment of COPD Exacerbations Requiring Hospitalization 
COPD  2011;8(1):21-29.
Rationale
Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations.
Objective
We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization.
Methods
Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production.
Main Findings
Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75±2.19 vs. 3.86±3.06 days for zileuton vs. placebo, p=0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p=0.63) despite a decline in urinary LTE4 levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine −1.38± 1.19 vs. 0.14±1.51, p<0.0001) and 72 hours (−1.32±2.08 vs. 0.26±1.93, p<0.006). Adverse events were similar in both groups.
Principal Conclusions
While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE4 levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement.
doi:10.3109/15412555.2010.540273
PMCID: PMC3775706  PMID: 21299475
Chronic Obstructive Pulmonary Disease (COPD); Acute exacerbation of COPD (AECOPD); Leukotrienes; Zileuton; Clinical trial
5.  Effect of Partner Violence in Adolescence and Young Adulthood on Blood Pressure and Incident Hypertension 
PLoS ONE  2014;9(3):e92204.
Intimate partner violence has adverse health consequences, but little is known about its association with hypertension. This study investigates sex differences in the relationship between intimate partner violence and blood pressure outcomes. Data included 9,699 participants from waves 3 (2001–02) and 4 (2008–09) of the National Longitudinal Study of Adolescent Health (51% female). Systolic (SBP) and diastolic (DBP) blood pressure and incident hypertension (SBP≥140 mmHg, DBP≥90 mmHg, or taking antihypertensive medication) were ascertained at wave 4. Intimate partner violence was measured at wave 3 with 8 items from the revised Conflict Tactics Scales. Separate victimization and perpetration scores were calculated. Sex-specific indicators of severe victimization and perpetration were created using the 66th percentile among those exposed as a cut point. Sex-specific, linear and logistic regression models were developed adjusting for age, race, financial stress, and education. Thirty-three percent of men and 47% of women reported any intimate partner violence exposure; participants were categorized as having: no exposure, moderate victimization and / or perpetration only, severe victimization, severe perpetration, and severe victimization and perpetration. Men experiencing severe perpetration and victimization had a 2.66 mmHg (95% CI: 0.05, 5.28) higher SBP and a 59% increased odds (OR: 1.59, 95% CI: 1.07, 2.37) of incident hypertension compared to men not exposed to intimate partner violence. No other category of violence was associated with blood pressure outcomes in men. Intimate partner violence was not associated with blood pressure outcomes in women. Intimate partner violence may have long-term consequences for men's hemodynamic health. Screening men for victimization and perpetration may assist clinicians to identify individuals at increased risk of hypertension.
doi:10.1371/journal.pone.0092204
PMCID: PMC3962399  PMID: 24658452
6.  The Relation of Serum Myeloperoxidase to Disease Progression and Mortality in Patients with Chronic Obstructive Pulmonary Disease (COPD) 
PLoS ONE  2013;8(4):e61315.
Myeloperoxidase is a strong oxidant stored in primary granules of neutrophils with potent antibacterial and proatherogenic properties. Myeloperoxidase has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the relationship of myeloperoxidase to health outcomes in COPD is not well known. We measured serum myeloperoxidase levels from 4,677 subjects with mild to moderate airflow limitation in the Lung Health Study. Using a Cox proportional hazards model, we determined the relationship of serum myeloperoxidase concentration to the risk of all-cause and disease specific causes of mortality. We found that serum myeloperoxidase concentrations were significantly related to accelerated decline in forced expiratory volume in 1 second (FEV1) over 11 years of follow-up (p<0.0001), and this association persisted after adjustments for age, sex, race, baseline FEV1, and smoking status (p = 0.048). Serum myeloperoxidase concentrations were also associated with increased risk of cardiovascular mortality (p = 0.036). Individuals in the highest quintile of myeloperoxidase had a hazard ratio of cardiovascular mortality of 1.90 (95% confidence interval 1.00–3.58; p = 0.049) compared with those in the lowest quintile, which was particularly notable in patients who continued to smoke (adjusted p-value of 0.0396). However, serum myeloperoxidase concentration was not related to total mortality, respiratory mortality, or deaths from malignancies. In conclusion, increased serum myeloperoxidase levels are associated with rapid lung function decline and poor cardiovascular outcomes in COPD patients, which support the emerging role of myeloperoxidase in the pathogenesis of COPD progression and cardiovascular disease.
doi:10.1371/journal.pone.0061315
PMCID: PMC3630209  PMID: 23637811
7.  Vitamin D Levels and Risk of Acute Exacerbations of Chronic Obstructive Pulmonary Disease 
Rationale: Low blood levels of 25-hydroxyvitamin D (25[OH]D) have been associated with a higher risk of respiratory infections in general populations and higher risk of exacerbations of lung disease in people with asthma. We hypothesized that low blood levels of 25(OH)D in patients with chronic obstructive pulmonary disease (COPD) would be associated with an increased risk of acute exacerbations of COPD (AECOPD).
Objectives: To determine if baseline 25(OH)D levels relate to subsequent AECOPD in a cohort of patients at high risk for AECOPD.
Methods: Plasma 25(OH)D was measured at baseline in 973 participants on entry to a 1-year study designed to determine if daily azithromycin decreased the incidence of AECOPD. Relationships between baseline 25(OH)D and AECOPD over 1 year were analyzed with time to first AECOPD as the primary outcome and exacerbation rate as the secondary outcome.
Measurements and Main Results: In this largely white (85%) sample of North American patients with severe COPD (mean FEV1 1.12L; 40% of predicted), mean 25(OH)D was 25.7 ± 12.8 ng/ml. A total of 33.1% of participants were vitamin D insufficient (≥20 ng/ml but <30 ng/ml); 32% were vitamin D deficient (<20 ng/ml); and 8.4% had severe vitamin D deficiency (<10 ng/ml). Baseline 25(OH)D levels had no relationship to time to first AECOPD or AECOPD rates.
Conclusions: In patients with severe COPD, baseline 25(OH)D levels are not predictive of subsequent AECOPD.
Clinical trial registered with www.clinicaltrials.gov (NCT00119860).
doi:10.1164/rccm.201109-1644OC
PMCID: PMC3297108  PMID: 22077070
chronic obstructive pulmonary disease; vitamin D; exacerbations
8.  Does nicotine replacement therapy cause cancer? Evidence from the Lung Health Study 
Nicotine & Tobacco Research  2009;11(9):1076-1082.
Introduction
Recent genetic evidence has implicated nicotine as a possible cause of cancer, suggesting the need to examine the potential contributions of nicotine itself to cancer versus the confounding effects of addiction and thus exposures to known carcinogens. The objective of this study was to examine the relationship between nicotine replacement therapy, smoking, and cancer outcomes.
Methods
The Lung Health Study enrolled 5,887 participants in a randomized trial to prevent chronic obstructive pulmonary disease. The present study used surveillance data on 3,320 intervention participants who enrolled in the Lung Health Study for 5 years and who were then followed by the Lung Cancer Substudy for 7.5 years. Nicotine replacement therapy use and smoking exposure were recorded during the 5-year Lung Health Study trial. Surveillance for lung cancer, gastrointestinal cancer (including oral cancers), and all cancers began following the Lung Health Study.
Results
Adjusted Cox proportional hazards regressions assessed the hazards of nicotine replacement therapy and smoking for each diagnosis group. In the adjusted models for lung cancer, nicotine replacement therapy alone was not a significant predictor (p = .57), while smoking during the Lung Health Study was a significant predictor (p = .03). When nicotine replacement therapy and smoking were entered in the same model, nicotine replacement therapy remained not significant (p = .25) and smoking was clearly significant (p = .02). Nicotine replacement therapy and smoking were not significant predictors of cancer in the models for gastrointestinal cancer or all cancers.
Discussion
Although the surveillance time was short, smoking predicted cancer in this analysis and nicotine replacement therapy did not.
doi:10.1093/ntr/ntp104
PMCID: PMC2725009  PMID: 19571249
9.  Serum PARC/CCL-18 Concentrations and Health Outcomes in Chronic Obstructive Pulmonary Disease 
Rationale: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum.
Objectives: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality.
Methods: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study.
Measurements and Main Results: Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort.
Conclusions: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.
Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
doi:10.1164/rccm.201008-1220OC
PMCID: PMC3114051  PMID: 21216880
biomarker; chronic obstructive pulmonary disease; PARC/CCL-18; chemokine
10.  The Relationship between Telomere Length and Mortality in Chronic Obstructive Pulmonary Disease (COPD) 
PLoS ONE  2012;7(4):e35567.
Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV1 and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy “mid-life” volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy “mid-life” volunteers (p<.001). Compared to individuals in the 4th quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.
doi:10.1371/journal.pone.0035567
PMCID: PMC3338848  PMID: 22558169
11.  Risk for Hospital Readmission following Bariatric Surgery 
PLoS ONE  2012;7(3):e32506.
Background and Objectives
Complications resulting in hospital readmission are important concerns for those considering bariatric surgery, yet present understanding of the risk for these events is limited to a small number of patient factors. We sought to identify demographic characteristics, concomitant morbidities, and perioperative factors associated with hospital readmission following bariatric surgery.
Methods
We report on a prospective observational study of 24,662 patients undergoing primary RYGB and 26,002 patients undergoing primary AGB at 249 and 317 Bariatric Surgery Centers of Excellence (BSCOE), respectively, in the United States from January 2007 to August 2009.
Data were collected using standardized assessments of demographic factors and comorbidities, as well as longitudinal records of hospital readmissions, complications, and mortality.
Results
The readmission rate was 5.8% for RYGB and 1.2% for AGB patients 30 days after discharge. The greatest predictors for readmission following RYGB were prolonged length of stay (adjusted odds ratio [OR], 2.3; 95% confidence interval [CI], 2.0–2.7), open surgery (OR, 1.8; CI, 1.4–2.2), and pseudotumor cerebri (OR, 1.6; CI, 1.1–2.4). Prolonged length of stay (OR, 2.3; CI, 1.6–3.3), history of deep venous thrombosis or pulmonary embolism (OR, 2.1; CI, 1.3–3.3), asthma (OR, 1.5; CI, 1.1–2.1), and obstructive sleep apnea (OR, 1.5; CI, 1.1–1.9) were associated with the greatest increases in readmission risk for AGB. The 30-day mortality rate was 0.14% for RYGB and 0.02% for AGB.
Conclusion
Readmission rates are low and mortality is very rare following bariatric surgery, but risk for both is significantly higher after RYGB. Predictors of readmission were disparate for the two procedures. Results do not support excluding patients with certain comorbidities since any reductions in overall readmission rates would be very small on the absolute risk scale. Future research should evaluate the efficacy of post-surgical managed care plans for patients at higher risk for readmission and adverse events.
doi:10.1371/journal.pone.0032506
PMCID: PMC3296721  PMID: 22412881
12.  Predictors of Attendance and Dropout at the Lung Health Study 11-Year Follow-Up 
Contemporary clinical trials  2006;28(1):25-32.
Participant attrition and attendance at follow-up were examined in a multicenter, randomized, clinical trial. The Lung Health Study (LHS) enrolled a total of 5, 887 adults to examine the impact of smoking cessation coupled with the use of an inhaled bronchodilator on chronic obstructive pulmonary disease (COPD). Of the initial LHS 1 volunteers still living at the time of enrolment in LHS 3 (5,332), 4,457 (84%) attended the LHS 3 clinic visit, a follow-up session to determine current smoking status and lung function. The average period between the beginning of LHS 1 and baseline interview for LHS 3 was 11 years. In univariate analyses, attenders were older, more likely female, more likely to be married, smoked fewer cigarettes per day, and were more likely to have children who smoked at the start of LHS 1 than non-attenders. Attenders were also less likely to experience respiratory symptoms, such as cough, but had decreased baseline lung function compared with non-attenders. Volunteers recruited via mass mailing were more likely to attend the long-term follow-up visit. Those recruited by public site, worksite, or referral methods were less likely to attend. In multivariate models, age, gender, cigarettes smoked per day, married status, and whether participants’ children smoked were identified as significant predictors of attendance versus non-attendance at LHS 3 using stepwise logistic regression. Treatment condition (smoking intervention or usual care) was not a significant predictor of attendance at LHS 3. Older females who smoked less heavily were most likely to participate. These findings may be applied to improve participant recruitment and retention in future clinical trials.
doi:10.1016/j.cct.2006.08.01
PMCID: PMC2562880  PMID: 17015043
subject attrition; participation; predictors; clinical trial; smoking cessation; Lung Health Study
13.  Vitamin D Status and Longitudinal Lung Function Decline in the Lung Health Study 
Low vitamin D blood levels are postulated to be a risk factor for worse lung function, largely based on cross-sectional data. We sought to use longitudinal data to test the hypothesis that baseline plasma 25-hydroxyvitamin D [25(OH)D] is lower in subjects with more rapid lung function decline, compared to those with slow lung function decline.
We conducted a nested, matched case-control study in the Lung Health Study 3 cohort. Cases and controls were continuous smokers with rapid and slow lung function decline, respectively, over approximately 6 years of follow-up. We compared baseline 25(OH)D levels between cases and controls, matching on date of blood draw and clinical center.
Among 196 subjects, despite rapid and slow decliners experiencing strikingly and significantly different rates of decline of forced expiratory volume in one second (−152 vs. −0.3 mL/year; p<0.001), there was no significant difference in baseline 25(OH)D levels (25.0 vs. 25.9 ng/mL; p=0.54). There was a high prevalence of vitamin D insufficiency (35%) and deficiency (31%); only 4% had a normal 25(OH)D level in the winter.
Although vitamin D insufficiency and deficiency are common among continuous smokers with established mild to moderate COPD, baseline 25(OH)D levels are not predictive of subsequent lung function decline.
doi:10.1183/09031936.00146509
PMCID: PMC3070416  PMID: 20595151
Pulmonary Disease, Chronic Obstructive; Smoking; Spirometry; Vitamin D
14.  Effect of heme oxygenase-1 polymorphisms on lung function and gene expression 
BMC Medical Genetics  2011;12:117.
Background
Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.
Methods
We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.
Results
We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.
Conclusions
We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.
doi:10.1186/1471-2350-12-117
PMCID: PMC3180266  PMID: 21902835
Heme oxygenase; polymorphism; chronic obstructive pulmonary disease
15.  Effect of gene environment interactions on lung function and cardiovascular disease in COPD 
Background:
The objective of this study was to determine if gene-environment interactions between cigarette smoking and interleukin-6 (IL6), interferon-γ (IFNG), interleukin-1β (IL1B), or interleukin-1 receptor antagonist (IL1RN) single nucleotide polymorphisms are associated with lung function decline and cardiovascular disease in chronic obstructive pulmonary disease (COPD).
Methods:
Single nucleotide polymorphisms (SNPs) in IL6, IFNG, IL1B, and IL1RN were genotyped in the Lung Health Study and correlated with rate of decline of forced expiratory volume in 1 second (FEV1) over 5 years, baseline FEV1, serum protein levels, cardiovascular disease, and interactions with smoking.
Results:
The IL6 rs2069825 single nucleotide polymorphism was associated with the rate of decline of prebronchodilator FEV1 (P = 0.049), and was found to have a significant interaction (P = 0.004) with mean number of cigarettes smoked per day. There was also a significant interaction of IFNG rs2069727 with smoking on prebronchodilator (P = 0.008) and postbronchodilator (P =0.01) FEV1. The IL6 polymorphism was also associated with cardiovascular disease in heterozygous individuals (P = 0.044), and was found to have a significant interaction with smoking (P = 0.024). None of the genetic variants were associated with their respective serum protein levels.
Conclusion:
The results suggest interactions of IL6 rs2069825 and IFNG rs2069727 single nucleotide polymorphisms with cigarette smoking on measures of lung function. The IL6 rs2069825 single nucleotide polymorphism also interacted with smoking to affect the risk of cardiovascular disease in COPD patients.
doi:10.2147/COPD.S18279
PMCID: PMC3144847  PMID: 21814463
gene-environment interactions; interleukin-6; forced expiratory volume in one second; cardiovascular disease; chronic obstructive pulmonary disease
16.  Aquaporin 5 Polymorphisms and Rate of Lung Function Decline in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2010;5(12):e14226.
Rationale
Aquaporin-5 (AQP5) can cause mucus overproduction and lower lung function. Genetic variants in the AQP5 gene might be associated with rate of lung function decline in chronic obstructive pulmonary disease (COPD).
Methods
Five single nucleotide polymorphisms (SNPs) in AQP5 were genotyped in 429 European American individuals with COPD randomly selected from the NHLBI Lung Health Study. Mean annual decline in FEV1 % predicted, assessed over five years, was calculated as a linear regression slope, adjusting for potential covariates and stratified by smoking status. Constructs containing the wildtype allele and risk allele of the coding SNP N228K were generated using site-directed mutagenesis, and transfected into HBE-16 (human bronchial epithelial cell line). AQP5 abundance and localization were assessed by immunoblots and confocal immunofluoresence under control, shear stress and cigarette smoke extract (CSE 10%) exposed conditions to test for differential expression or localization.
Results
Among continuous smokers, three of the five SNPs tested showed significant associations (0.02>P>0.004) with rate of lung function decline; no associations were observed among the group of intermittent or former smokers. Haplotype tests revealed multiple association signals (0.012>P>0.0008) consistent with the single-SNP results. In HBE16 cells, shear stress and CSE led to a decrease in AQP5 abundance in the wild-type, but not in the N228K AQP5 plasmid.
Conclusions
Polymorphisms in AQP5 were associated with rate of lung function decline in continuous smokers with COPD. A missense mutation modulates AQP-5 expression in response to cigarette smoke extract and shear stress. These results suggest that AQP5 may be an important candidate gene for COPD.
doi:10.1371/journal.pone.0014226
PMCID: PMC2997058  PMID: 21151978
17.  Superior Immune Response to Protein-Conjugate versus Free Pneumococcal Polysaccharide Vaccine in Chronic Obstructive Pulmonary Disease 
Rationale: Debate exists about the immunogenicity and protective efficacy of antibodies produced by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary disease (COPD). The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) induces a more robust immune response than PPSV23 in healthy elderly adults.
Objectives: We hypothesized that serotype-specific IgG antibody concentration and functional antibody activity would be superior after PCV7 vaccination compared with PPSV23 in moderate to severe COPD. We also posited that older age and prior PPSV23 vaccination would be associated with reduced vaccine responsiveness.
Methods: One hundred twenty patients with COPD were randomized to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations were determined by ELISA; functional antibody activity was assayed with a standardized opsonophagocytosis assay and reported as an opsonization killing index (OPK). Increases in serotype-specific IgG and OPK at 1 month post vaccination were compared within and between vaccine groups.
Measurements and Main Results: Both vaccines were well tolerated. Within each study group, postvaccination IgG and OPK were higher than baseline (P < 0.01) for all serotypes. Adjusted for baseline levels, postvaccination IgG was higher in the PCV7 group than the PPSV23 group for all seven serotypes, reaching statistical significance for five (P < 0.05). PCV7 resulted in a higher OPK for six of seven serotypes (statistically greater for four) compared with PPSV23. In multivariate analyses, younger age, vaccine naivety, and receipt of PCV7 were associated with increased OPK responses.
Conclusions: PCV7 induces a superior immune response at 1 month post vaccination compared with PPSV23 in COPD. Older age and prior PPSV23 reduce vaccine responsiveness.
Clinical trial registered with www.clinicaltrials.gov (NCT00457977).
doi:10.1164/rccm.200903-0488OC
PMCID: PMC2742743  PMID: 19556517
pneumococcal vaccines; vaccination, COPD; immune responses; immunization
18.  Transforming Growth Factor-β Receptor-3 Is Associated with Pulmonary Emphysema 
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-β receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV1 (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.
doi:10.1165/rcmb.2008-0427OC
PMCID: PMC2742752  PMID: 19131638
betaglycan; chronic obstructive pulmonary disease; computed tomography; linkage; single nucleotide polymorphism
19.  Associations of IL6 polymorphisms with lung function decline and COPD 
Thorax  2009;64(8):698-704.
Background
Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which likely plays an important role in the pathogenesis of COPD. There is a functional single nucleotide polymorphism (SNP), −174G/C, in the promoter region of IL6. We hypothesized that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers.
Methods
Seven and 5 SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in one second (FEV1) over 5 years and baseline FEV1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of 9 IL6 SNPs was genotyped in 389 COPD cases from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS).
Results
In the LHS, three IL6 SNPs were associated with FEV1 decline (0.023 ≤ P ≤ 0.041 in additive models). Among them the IL6_−174C allele was associated with rapid decline of lung function. The association was more significant in a genotype-based analysis (P = 0.006). In the NETT-NAS study, IL6_−174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_−174G/C, were associated with susceptibility to COPD (0.01 ≤ P ≤ 0.04 in additive genetic models).
Conclusion
Our results suggest that the IL6_−174G/C SNP is associated with rapid decline of FEV1 and susceptibility to COPD in smokers.
doi:10.1136/thx.2008.111278
PMCID: PMC2859187  PMID: 19359268
genetic polymorphism; IL6; forced expiratory volume in one second (FEV1); lung function; chronic obstructive pulmonary disease (COPD)
20.  Eosinophil and T cell markers predict functional decline in COPD patients 
Respiratory Research  2009;10(1):113.
Background
The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease.
Methods
Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines.
Results and Discussion
Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05).
Conclusion
These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.
doi:10.1186/1465-9921-10-113
PMCID: PMC2785783  PMID: 19925666
21.  Variability of Spirometry in Chronic Obstructive Pulmonary Disease 
Objective: Our goal is to determine short-term intraindividual biologic and measurement variability in spirometry of patients with a wide range of stable chronic obstructive pulmonary disease severity, using datasets from the National Emphysema Treatment Trial (NETT) and the Lung Health Study (LHS). This may be applied to determine criteria that can be used to assess a clinically meaningful change in spirometry.
Methods: A total of 5,886 participants from the LHS and 1,215 participants from the NETT performed prebronchodilator spirometry during two baseline sessions. We analyzed varying criteria for absolute and percent change of FEV1 and FVC to determine which criterion was met by 90% of the participants.
Results: The mean ± SD FEV1 for the initial session was 2.64 ± 0.60 L (75.1 ± 8.8% predicted) for the LHS and 0.68 ± 0.22 L (23.7 ± 6.5% predicted) for the NETT. The mean ± SD number of days between test sessions was 24.9 ± 17.1 for the LHS and 85.7 ± 21.7 for the NETT. As the degree of obstruction increased, the intersession percent difference of FEV1 increased. However, the absolute difference between tests remained relatively constant despite the severity of obstruction (0.106 ± 0.10 L). Over 90% of participants had an intersession FEV1 difference of less than 225 ml irrespective of the severity of obstruction.
Conclusions: Absolute changes in FEV1 rather than percent change should be used to determine whether patients with chronic obstructive pulmonary disease have improved or worsened between test sessions.
doi:10.1164/rccm.200506-975OC
PMCID: PMC2662942  PMID: 16497996
forced expiratory volume; obstructive lung diseases; reproducibility of measurements; spirometry; vital capacity
22.  Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study 
Respiratory Research  2006;7(1):76.
Background
Alpha-defensins, which are major constituents of neutrophil azurophilic granules, and beta-defensins, which are expressed in airway epithelial cells, could contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying cigarette smoke-induced and infection-induced inflammatory reactions leading to lung injury. In Japanese and Chinese populations, two different beta-defensin-1 polymorphisms have been associated with chronic obstructive pulmonary disease phenotypes. We conducted population-based association studies to test whether alpha-defensin and beta-defensin polymorphisms influenced smokers' susceptibility to lung function decline and susceptibility to lower respiratory infection in two groups of white participants in the Lung Health Study (275 = fast decline in lung function and 304 = no decline in lung function).
Methods
Subjects were genotyped for the alpha-defensin-1/alpha-defensin-3 copy number polymorphism and four beta-defensin-1 polymorphisms (G-20A, C-44G, G-52A and Val38Ile).
Results
There were no associations between individual polymorphisms or imputed haplotypes and rate of decline in lung function or susceptibility to infection.
Conclusion
These findings suggest that, in a white population, the defensin polymorphisms tested may not be of importance in determining who develops abnormally rapid lung function decline or is susceptible to developing lower respiratory infections.
doi:10.1186/1465-9921-7-76
PMCID: PMC1523340  PMID: 16700921
23.  Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema 
PLoS ONE  2013;8(2):e56352.
Rationale
Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema.
Methods
Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period.
Main Results
Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline.
Conclusions
MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease.
doi:10.1371/journal.pone.0056352
PMCID: PMC3575373  PMID: 23441181
24.  A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region as a Risk Factor for Age-Dependent Nicotine Addiction 
PLoS Genetics  2008;4(7):e1000125.
People who begin daily smoking at an early age are at greater risk of long-term nicotine addiction. We tested the hypothesis that associations between nicotinic acetylcholine receptor (nAChR) genetic variants and nicotine dependence assessed in adulthood will be stronger among smokers who began daily nicotine exposure during adolescence. We compared nicotine addiction—measured by the Fagerstrom Test of Nicotine Dependence—in three cohorts of long-term smokers recruited in Utah, Wisconsin, and by the NHLBI Lung Health Study, using a candidate-gene approach with the neuronal nAChR subunit genes. This SNP panel included common coding variants and haplotypes detected in eight α and three β nAChR subunit genes found in European American populations. In the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the CHRNA5-A3-B4 locus were associated with nicotine dependence severity (p = 2.0×10−5; odds ratio = 1.82; 95% confidence interval 1.39–2.39) in subjects who began daily smoking at or before the age of 16, an exposure period that results in a more severe form of adult nicotine dependence. A substantial shift in susceptibility versus protective diplotype frequency (AA versus BC = 17%, AA versus CC = 27%) was observed in the group that began smoking by age 16. This genetic effect was not observed in subjects who began daily nicotine use after the age of 16. These results establish a strong mechanistic link among early nicotine exposure, common CHRNA5-A3-B4 haplotypes, and adult nicotine addiction in three independent populations of European origins. The identification of an age-dependent susceptibility haplotype reinforces the importance of preventing early exposure to tobacco through public health policies.
Author Summary
Tobacco use is a global health care problem, and persistent smoking takes an enormous toll on individual health. The onset of daily smoking in adolescence is related to chronic use and severe nicotine dependence in adulthood. Since nicotine is the key addictive chemical in tobacco, we tested the hypothesis that genetic variants within nicotinic acetylcholine receptors will influence the severity of addiction measured in adulthood. Using genomic resequencing to define the patterns of variation found in these candidate genes, we observed that common haplotypes in the CHRNA5-A3-B4 gene cluster are associated with adult nicotine addiction, specifically among those who began daily smoking before age 17. We show that in populations of European origins, one haplotype is a risk factor for dependence, one is protective, and one is neutral. These observations suggest that genetic determinants expressed during human adolescence contribute to the risk of lifetime addiction severity produced from early onset of cigarette use. Because disease risk from the adverse health effects of tobacco smoke is related to lifetime tobacco exposure, the finding that an age-dependent effect of these haplotypes has a strong influence on lifetime smoking behavior reinforces the public health significance of delaying smoking onset.
doi:10.1371/journal.pgen.1000125
PMCID: PMC2442220  PMID: 18618000

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