Search

Wood burning is a major source of ambient particulate matter (PM) and has been epidemiologically linked to adverse pulmonary health effects, however the impact of fuel and burning conditions on PM properties has not been investigated systematically. Here, we employed our recently developed integrated methodology to characterize the physicochemical and biological properties of emitted PM as a function of three common hardwoods (oak, cherry, mesquite) and three representative combustion conditions (flaming, smoldering, incomplete). Differences in PM and off-gas emissions (aerosol number/mass concentrations; carbon monoxide; volatile organic compounds) as well as inorganic elemental composition and organic carbon functional content of PM 0.1 were noted between wood types and combustion conditions, although the combustion scenario exerted a stronger influence on the emission profile. More importantly, flaming combustion PM 0.1 from all hardwoods significantly stimulated the promoter activity of Sterile Alpha Motif (SAM) pointed domain containing ETS (E-twenty-six) Transcription Factor (SPDEF) in human embryonic kidney 293 (HEK-293 T) cells, a biomarker for mucin gene expression associated with mucus production in pulmonary diseases. However, no bioactivity was observed for smoldering and incomplete combustion, which was likely driven by differences in the organic composition of PM 0.1 . Detailed chemical speciation of organic components of wood smoke is warranted to identify the individual compounds that drive specific biological responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone., Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?, Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10 -6 ) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2)., Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10 -8 ) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent., Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets., Research Question: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations?, Study Design and Methods: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations., Results: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations., Interpretation: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations., Trial Registry: ClinicalTrials.gov; No.: NCT01969344; URL: www., Clinicaltrials: gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, -5.7%; adjusted 95% CI, -8.8% to -2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure., (© 2022 by The American Society of Hematology.)

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.

IFN-γ is known as a pro-inflammatory cytokine, but can also block inflammation in certain chronic diseases although the underlying mechanisms are poorly understood. We found that IFN-γ rapidly induced Noxa expression and that extent of inflammation by repeated house dust mite exposure was enhanced in noxa -/- compared with noxa +/+ mice. Noxa expression blocked transforming necrosis factor alpha (TNF-α)-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of pro-inflammatory cytokines. Noxa did not affect TNF-α-induced IκBα phosphorylation but the degradation of 48-chain-ubiquitylated IκBα. The Cys25 of Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were required for blocking the degradation of ubiquitylated IκBα. Because phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway epithelia. These mice showed protection from allergen-induced inflammation and mucous cell metaplasia by blocking nuclear translocation of NF-κB. Further, we identified a Noxa-derived peptide that prolonged degradation of 48-chain-ubiquitylated IκBα, blocked nuclear translocation of NF-κB, and reduced allergen-induced inflammation in mice. These results suggest that the anti-inflammatory role of the Noxa protein may be restricted to airway epithelial cells and the use of Noxa for therapy of chronic lung diseases may be associated with reduced side effects.

Background: Smoking is associated with impaired health-related quality of life (HRQL) across all populations. Because decline in lung function and risk for COPD are lower in New Mexican Hispanic smokers compared with their non-Hispanic white (NHW) counterparts, the goal of this study was to ascertain whether HRQL differs between these two racial/ethnic groups and determine the factors that contribute to this difference., Methods: We compared the score results of the Medical Outcomes Short-Form 36 Health Survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) in 378 Hispanic subjects and 1,597 NHW subjects enrolled in the Lovelace Smokers' Cohort (LSC) from New Mexico. The associations of race/ethnicity with SGRQ and SF-36 were assessed by using multivariable regression., Results: Physical functioning (difference, -4.5; P = .0008) but not mental health or role emotional domains of the SF-36 was worse in Hispanic smokers than in their NWH counterparts in multivariable analysis. SGRQ total score and its activity and impact subscores were worse in Hispanic (vs NHW) smokers after adjustment for education level, current smoking, pack-years smoked, BMI, number of comorbidities, and FEV 1 % predicted (difference range, 2.9-5.0; all comparisons, P ≤ .001). Although the difference in the SGRQ activity domain was above the clinically important difference of four units, the total score was not., Conclusions: New Mexican Hispanic smokers have clinically relevant, lower HRQL than their NHW counterparts. A perception of diminished physical functioning and impairment in daily life activities contribute to the poorer HRQL among Hispanic subjects., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: COPD includes the chronic bronchitis (CB) and emphysema phenotypes. Although it is generally assumed that emphysema or chronic airflow obstruction (CAO) is associated with worse quality of life (QOL) than is CB, this assumption has not been tested., Methods: The current study's analyses from the Lovelace Smokers' Cohort (LSC) were validated in the COPD Gene Cohort (COPDGene). CB without CAO (CB only) was defined as self-reported cough productive of phlegm for ≥ 3 mo/y for 2 consecutive years and postbronchodilator FEV1/FVC ≥ 70%. CAO without CB (CAO only) was defined as a postbronchodilator FEV1/FVC < 70% with no evidence of CB. QOL outcomes were obtained from the St. George's Respiratory Questionnaire (SGRQ) and the 36-Item Short Form Health Survey (SF-36) questionnaires. A priori covariates included age, sex, pack-years of smoking, current smoking, and FEV1., Results: Smokers with CB without CAO (LSC = 341; COPDGene = 523) were younger and had a greater BMI and less smoking exposure than did those with CAO only (LSC = 302; COPDGene = 2,208). Compared with the latter group, QOL scores were worse for those with CB only. Despite similar SGRQ Activity and SF-36 Role Physical and Physical Functioning, SGRQ Symptoms and Impact scores and SF-36 emotional and social measures were worse in the CB-only group, in both cohorts. After adjustment for covariates, the CB-only group remained a significant predictor for "worse" symptoms and emotional and social measures., Conclusions: To our knowledge, this analysis is the first to suggest that among subjects with COPD, those with CB only present worse QOL symptoms and mental well-being than do those with CAO only.

Introduction: Lung cancer and chronic obstructive pulmonary disease (COPD) share environmental risk factors. COPD also increases the risk of lung cancer; however, the molecular mechanisms are unclear., Methods: An epigenome-wide association study of lung tumors and cancer-free lung tissue (CFLT) pairs from non-small-cell lung cancer cases with (n = 18) or without (n = 17) COPD was conducted using the HumanMethylation450 beadchip (HM450K). COPD-associated methylation of top-ranked genes was confirmed in a larger sample set, independently validated, and their potential as sputum-based biomarkers was investigated., Results: Methylation of CCDC37 and MAP1B was more prevalent in lung tumors from COPD than non-COPD cases [54 of 71 (76%) versus 20 of 46 (43%), p = 0.0013] and [48 of 71 (68%) versus 17 of 46 (37%), p = 0.0035], respectively, after adjustment for age, sex, smoking status, and tumor histology. HM450K probes across CCDC37 and MAP1B promoters showed higher methylation in tumors than CFLT with the highest methylation seen in tumors from COPD cases (p < 0.05). These results were independently validated using The Cancer Genome Atlas data. CCDC37 methylation was more prevalent in sputum from COPD than non-COPD smokers (p < 0.005) from two cohorts. CCDC37 and MAP1B expression was dramatically repressed in tumors and CFLT from COPD than non-COPD cases, p less than 0.02., Conclusions: The reduced expression of CCDC37 and MAP1B associated with COPD likely predisposes these genes to methylation that in turn, may contribute to lung cancer.

Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)-exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Whether Native American ancestry (NAA) is associated with COPD or lung function in a racially admixed Hispanic population is unknown., Methods: We recruited 578 Costa Ricans with and without COPD into a hybrid case-control/family-based cohort, including 316 members of families of index case subjects. All participants completed questionnaires and spirometry and gave a blood sample for DNA extraction. Genome-wide genotyping was conducted with the Illumina Human610-Quad and HumanOmniExpress BeadChip kits (Illumina Inc), and individual ancestral proportions were estimated from these genotypic data and reference panels. For unrelated individuals, linear or logistic regression was used for the analysis of NAA and COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage II or greater) or lung function. For extended families, linear mixed models and generalized estimating equations were used for the analysis. All models were adjusted for age, sex, educational level, and smoking behavior; models for FEV1 were also adjusted for height., Results: The average proportion of European, Native American, and African ancestry among participants was 62%, 35%, and 3%, respectively. After adjustment for current smoking and other covariates, NAA was inversely associated with COPD (OR per 10% increment, 0.55; 95% CI, 0.41-0.75) but positively associated with FEV1, FVC, and FEV1/FVC. After additional adjustment for pack-years of smoking, the association between NAA and COPD or lung function measures was slightly attenuated. We found that about 31% of the estimated effect of NAA on COPD is mediated by pack-years of smoking., Conclusions: NAA is inversely associated with COPD but positively associated with FEV1 or FVC in Costa Ricans. Ancestral effects on smoking behavior partly explain the findings for COPD but not for FEV1 or FVC.

Objective: Cigarette smoking is the most important risk factor for COPD in the United States. Host factors that influence the rapid rate of FEV1 decline in smokers and how decline rate influences risk for developing COPD are unknown. The aim of this study was to characterize the rate of FEV1 decline in ever smokers, compare the risk of incident COPD between those with rapid decline and others, and determine the effect of selected drugs on rapid decline., Methods: A total of 1,170 eligible ever smokers from the longitudinal Lovelace Smokers Cohort with repeat spirometry tests over a minimum follow-up period of 3 years (mean follow-up, 5.9 years) were examined, including 809 ever smokers without a spirometric abnormality at baseline. Longitudinal absolute decline in postbronchodilator FEV1 from the slope of the spirometric values over all examinations was annualized and classified as rapid (≥30 mL/y), normal (0-29.9 mL/y), or no (>0 mL/y) decline. Logistic regression and Kaplan-Meier survival curves were used for the analysis., Results: Approximately 32% of ever smokers exhibited rapid decline. Among ever smokers without a baseline spirometric abnormality, rapid decline was associated with an increased risk for incident COPD (OR, 1.88; P=.003). The use of angiotensin-converting enzyme (ACE) inhibitors at baseline examination was protective against rapid decline, particularly among those with comorbid cardiovascular disease, hypertension, or diabetes (ORs 0.48, 0.48, and 0.12, respectively; P≤.02 for all analyses)., Conclusions: Ever smokers with a rapid decline in FEV1 are at higher risk for COPD. Use of ACE inhibitors by smokers may protect against this rapid decline and the progression to COPD.

Objective: The epigenetic basis for human asthma is not well studied, particularly among older adults. This study investigated the methylation profiles in sputum DNA among older adults with asthma, using a population of smokers., Methods: This was a cross-sectional study using the Lovelace Smokers Cohort, a population of former and current smokers aged ≥ 40 years in New Mexico. One hundred eighty-four smokers with asthma were compared with 511 smoker control subjects with a similar smoking history, after carefully excluding those with COPD. Environmental exposures were assessed by a standard questionnaire. Postbronchodilator spirometry was performed. Induced sputum was analyzed for the methylation prevalence of 12 selected asthma-related genes using nested methylation-specific polymerase chain reaction assay., Results: Asthma was associated with a greater number of methylated genes and, specifically, with methylated protocadherin-20 gene in sputum DNA compared with control subjects with a similar smoking history. These associations remained significant after adjustment for covariates as well as Bonferroni correction. A synergistic interaction was noted between two methylated genes (protocadherin-20 and paired box protein transcription factor-5α) in sputum DNA on the odds for asthma (P = .009). Interestingly, the epigenetic-asthma associations were not explained by the environmental factors studied. Further, methylated genes in sputum DNA, including the protocadherin-20 gene, identified a symptomatically more severe asthma phenotype in a subgroup analysis., Conclusions: Asthma is associated with methylation of selected genes, such as protocadherin-20 gene, in sputum DNA. If future studies establish causality, novel demethylating interventions to prevent and treat asthma among older smokers may be possible.