Publications by authors named "Stephanie A Christenson"

46 Publications

Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease.

J Cachexia Sarcopenia Muscle 2021 Sep 15. Epub 2021 Sep 15.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach.

Methods: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data.

Results: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling.

Conclusions: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
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http://dx.doi.org/10.1002/jcsm.12782DOI Listing
September 2021

Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS.

Nat Commun 2021 08 26;12(1):5152. Epub 2021 Aug 26.

Department of Pathology, University of California, San Francisco, CA, USA.

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.
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http://dx.doi.org/10.1038/s41467-021-25040-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390461PMC
August 2021

High serum granulocyte-colony stimulating factor characterises neutrophilic COPD exacerbations associated with dysbiosis.

ERJ Open Res 2021 Jul 2;7(3). Epub 2021 Aug 2.

Biomarker Discovery OMNI, Genentech Inc., South San Francisco, CA, USA.

Introduction: COPD exacerbations are heterogeneous and can be triggered by bacterial, viral, or noninfectious insults. Exacerbations are also heterogeneous in neutrophilic or eosinophilic inflammatory responses. A noninvasive peripheral biomarker of COPD exacerbations characterised by bacterial/neutrophilic inflammation is lacking. Granulocyte-colony stimulating factor (G-CSF) is a key cytokine elevated during bacterial infection and mediates survival, proliferation, differentiation and function of neutrophils.

Objective: We hypothesised that high peripheral G-CSF would be indicative of COPD exacerbations with a neutrophilic and bacterial phenotype associated with microbial dysbiosis.

Methods: Serum G-CSF was measured during hospitalised exacerbation (day 0 or D0) and after 30 days of recovery (Day30 or D30) in 37 subjects. In a second cohort, serum and sputum cytokines were measured in 59 COPD patients during stable disease, at exacerbation, and at 2-weeks and 6-weeks following exacerbation.

Results: Serum G-CSF was increased during exacerbation in a subset of patients. These exacerbations were enriched for bacterial but not viral or type-2 biologies. The median serum G-CSF level was 1.6-fold higher in bacterial exacerbation compared to nonbacterial exacerbation (22 pg·mL 13 pg·mL, p=0.0007). Serum G-CSF classified bacterial exacerbations with an area under the curve (AUC) for the receiver operating characteristic (ROC) curve equal to 0.76. Exacerbations with a two-fold or greater increase in serum G-CSF were characterised by neutrophilic inflammation, with increased sputum and blood neutrophils, and high sputum interleukin (IL)-1β, IL-6 and serum amyloid A1 (SAA1) levels. These exacerbations were preceded by dysbiosis, with decreased microbiome diversity and enrichment of respiratory pathogens such as and . Furthermore, serum G-CSF at exacerbation classified neutrophilic-dysbiotic exacerbations (AUC for the ROC curve equal to 0.75).

Conclusions: High serum G-CSF enriches for COPD exacerbations characterised by neutrophilic inflammation with underlying bacterial dysbiosis.
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http://dx.doi.org/10.1183/23120541.00836-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326681PMC
July 2021

The sputum transcriptome better predicts COPD exacerbations after the withdrawal of inhaled corticosteroids than sputum eosinophils.

ERJ Open Res 2021 Jul 5;7(3). Epub 2021 Jul 5.

Dept of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Introduction: Continuing inhaled corticosteroid (ICS) use does not benefit all patients with COPD, yet it is difficult to determine which patients may safely sustain ICS withdrawal. Although eosinophil levels can facilitate this decision, better biomarkers could improve personalised treatment decisions.

Methods: We performed transcriptional profiling of sputum to explore the molecular biology and compared the predictive value of an unbiased gene signature sputum eosinophils for exacerbations after ICS withdrawal in COPD patients. RNA-sequencing data of induced sputum samples from 43 COPD patients were associated with the time to exacerbation after ICS withdrawal. Expression profiles of differentially expressed genes were summarised to create gene signatures. In addition, we built a Bayesian network model to determine coregulatory networks related to the onset of COPD exacerbations after ICS withdrawal.

Results: In multivariate analyses, we identified a gene signature (, , , , , ) associated with the time to first exacerbation after ICS withdrawal. The addition of this gene signature to a multiple Cox regression model explained more variance of time to exacerbations compared to a model using sputum eosinophils. The gene signature correlated with sputum eosinophil as well as macrophage cell counts. The Bayesian network model identified three coregulatory gene networks as well as sex to be related to an early late/nonexacerbation phenotype.

Conclusion: We identified a sputum gene expression signature that exhibited a higher predictive value for predicting COPD exacerbations after ICS withdrawal than sputum eosinophilia. Future studies should investigate the utility of this signature, which might enhance personalised ICS treatment in COPD patients.
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http://dx.doi.org/10.1183/23120541.00097-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255541PMC
July 2021

Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort.

Lancet Respir Med 2021 May 28. Epub 2021 May 28.

Marsico Lung Institute/Cystic Fibrosis and Pulmonary Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Background: We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD.

Methods: SPIROMICS was a multicentre, observational study in patients aged 40-80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344).

Findings: This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV and FEF, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04-1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV, FEV/FVC, FEF, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years.

Interpretation: These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents.

Funding: National Institutes of Health; National Heart, Lung, and Blood Institute.
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http://dx.doi.org/10.1016/S2213-2600(21)00079-5DOI Listing
May 2021

Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.

Genome Med 2021 04 21;13(1):66. Epub 2021 Apr 21.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.

Background: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

Methods: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

Results: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

Conclusions: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.
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http://dx.doi.org/10.1186/s13073-021-00866-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059115PMC
April 2021

Defining Resilience to Smoking Related Lung Disease: A Modified Delphi Approach from SPIROMICS.

Ann Am Thorac Soc 2021 Feb 25. Epub 2021 Feb 25.

UCSF, Division of Pulmonary and Critical Care Medicine, Department of Medicine and CVRI, San Francisco, California, United States.

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease that have minimal or no airflow obstruction.

Objectives: Develop a multi-dimensional definition of a lung-related "resilient smoker" that is useful in research studies; then identify a resilient smoker subgroup in the SPIROMICS cohort using this definition.

Methods: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ≥80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD.

Results: Consensus was achieved on 6 of 12 diagnostic items which include: cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in FEV1. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of C-reactive protein (CRP) and soluble tumor necrosis receptor factor1A (sTNFRSF1A) was lower in resilient than non-resilient smokers (P=0.02 and P=0.03).

Conclusions: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "non-resilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from non-resilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344).
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http://dx.doi.org/10.1513/AnnalsATS.202006-757OCDOI Listing
February 2021

Lung microbiota associations with clinical features of COPD in the SPIROMICS cohort.

NPJ Biofilms Microbiomes 2021 02 5;7(1):14. Epub 2021 Feb 5.

Division of Pulmonary/Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.
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http://dx.doi.org/10.1038/s41522-021-00185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865064PMC
February 2021

Current smoking with or without chronic bronchitis is independently associated with goblet cell hyperplasia in healthy smokers and COPD subjects.

Sci Rep 2020 11 18;10(1):20133. Epub 2020 Nov 18.

University of California San Francisco, San Francisco, CA, USA.

COPD, chronic bronchitis (CB) and active smoking have all been associated with goblet cell hyperplasia (GCH) in small studies. Active smoking is strongly associated with CB, but there is a disconnect between CB clinical symptoms and pathology. Chronic cough and sputum production poorly correlate with the presence of GCH or COPD. We hypothesized that the primary determinant of GCH in ever smokers with or without airflow obstruction is active smoking. Goblet Cell Density (GCD) was measured in 71 current or former smokers [32 subjects without COPD and 39 COPD subjects]. Endobronchial mucosal biopsies were stained with Periodic Acid Schiff-Alcian Blue, and GCD was measured as number of goblet cells/mm basement membrane. GCD was divided into tertiles based on log transformed values. LogGCD was greater in current smokers compared to former smokers. Those with classically defined CB or SGRQ defined CB had a greater log GCD compared to those without CB. Current smoking was independently associated with tertile 3 (high logGCD) whereas CB was not in multivariable regression when adjusting for lung function and demographics. These results suggest that GCH is induced by active smoke exposure and does not necessarily correlate with the clinical symptoms of CB.
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http://dx.doi.org/10.1038/s41598-020-77229-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674445PMC
November 2020

Upper airway gene expression reveals suppressed immune responses to SARS-CoV-2 compared with other respiratory viruses.

Nat Commun 2020 11 17;11(1):5854. Epub 2020 Nov 17.

Division of Infectious Diseases, University of California, San Francisco, CA, USA.

SARS-CoV-2 infection is characterized by peak viral load in the upper airway prior to or at the time of symptom onset, an unusual feature that has enabled widespread transmission of the virus and precipitated a global pandemic. How SARS-CoV-2 is able to achieve high titer in the absence of symptoms remains unclear. Here, we examine the upper airway host transcriptional response in patients with COVID-19 (n = 93), other viral (n = 41) or non-viral (n = 100) acute respiratory illnesses (ARIs). Compared with other viral ARIs, COVID-19 is characterized by a pronounced interferon response but attenuated activation of other innate immune pathways, including toll-like receptor, interleukin and chemokine signaling. The IL-1 and NLRP3 inflammasome pathways are markedly less responsive to SARS-CoV-2, commensurate with a signature of diminished neutrophil and macrophage recruitment. This pattern resembles previously described distinctions between symptomatic and asymptomatic viral infections and may partly explain the propensity for pre-symptomatic transmission in COVID-19. We further use machine learning to build 27-, 10- and 3-gene classifiers that differentiate COVID-19 from other ARIs with AUROCs of 0.981, 0.954 and 0.885, respectively. Classifier performance is stable across a wide range of viral load, suggesting utility in mitigating false positive or false negative results of direct SARS-CoV-2 tests.
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http://dx.doi.org/10.1038/s41467-020-19587-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673985PMC
November 2020

Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers.

Am J Respir Crit Care Med 2021 04;203(8):957-968

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah Hospitals and Clinics, Salt Lake City, Utah.

The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain. To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD. We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression. Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV and peripheral oxygen saturation ( < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema ( < 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) ( < 0.001). Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).
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http://dx.doi.org/10.1164/rccm.202006-2248OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048745PMC
April 2021

Plasma Cathelicidin is Independently Associated with Reduced Lung Function in COPD: Analysis of the Subpopulations and Intermediate Outcome Measures in COPD Study Cohort.

Chronic Obstr Pulm Dis 2020 Oct;7(4):370-381

Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina, Chapel Hill.

Ratrionale: The antimicrobial peptide cathelicidin, also known in humans as LL-37, is a defensin secreted by immune and airway epithelial cells. Deficiencies in this peptide may contribute to adverse pulmonary outcomes in chronic obstructive pulmonary disease (COPD).

Objectives: Using clinical and biological samples from the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we assessed the associations of plasma cathelicidin levels with cross-sectional and longitudinal COPD outcomes.

Methods: A total of 1609 SPIROMICS participants with COPD and available plasma samples were analyzed. Cathelicidin was modeled dichotomously (lowest quartile [< 50 ng/ml] versus highest 75% [≥ 50 ng/ml]) and continuously per 10 ng/ml. Fixed-effect multilevel regression analyses were used to assess associations between cathelicidin and cross-sectional as well as longitudinal lung function. The associations between cathelicidin and participant-reported retrospective and prospective COPD exacerbations were assessed via logistic regression.

Measurements And Main Results: Cathelicidin < 50 ng/ml (N=383) was associated with female sex, black race, and lower body mass index (BMI).At baseline,cathelicidin < 50 ng/ml was independently associated with 3.55% lower % predicted forced expiratory volume in 1 second (FEV)(95% confidence interval [CI] -6.22% to -0.88% predicted; =0.01), while every 10 ng/ml lower cathelicidin was independently associated with 0.65% lower % predicted FEV (95% CI -1.01% to -0.28% predicted; < 0.001). No independent associations with longitudinal lung function decline or participant-reported COPD exacerbations were observed.

Conclusions: Reduced cathelicidin is associated with lower lung function at baseline. Plasma cathelicidin may potentially identify COPD patients at increased risk for more severe lung disease.
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http://dx.doi.org/10.15326/jcopdf.7.4.2020.0142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883905PMC
October 2020

Contribution of Individual and Neighborhood Factors to Racial Disparities in Respiratory Outcomes.

Am J Respir Crit Care Med 2021 04;203(8):987-997

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.

Black adults have worse health outcomes compared with white adults in certain chronic diseases, including chronic obstructive pulmonary disease (COPD). To determine to what degree disadvantage by individual and neighborhood socioeconomic status (SES) may contribute to racial disparities in COPD outcomes. Individual and neighborhood-scale sociodemographic characteristics were determined in 2,649 current or former adult smokers with and without COPD at recruitment into SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). We assessed whether racial differences in symptom, functional, and imaging outcomes (St. George's Respiratory Questionnaire, COPD Assessment Test score, modified Medical Research Council dyspnea scale, 6-minute-walk test distance, and computed tomography [CT] scan metrics) and severe exacerbation risk were explained by individual or neighborhood SES. Using generalized linear mixed model regression, we compared respiratory outcomes by race, adjusting for confounders and individual-level and neighborhood-level descriptors of SES both separately and sequentially. After adjusting for COPD risk factors, Black participants had significantly worse respiratory symptoms and quality of life (modified Medical Research Council scale, COPD Assessment Test, and St. George's Respiratory Questionnaire), higher risk of severe exacerbations and higher percentage of emphysema, thicker airways (internal perimeter of 10 mm), and more air trapping on CT metrics compared with white participants. In addition, the association between Black race and respiratory outcomes was attenuated but remained statistically significant after adjusting for individual-level SES, which explained up to 12-35% of racial disparities. Further adjustment showed that neighborhood-level SES explained another 26-54% of the racial disparities in respiratory outcomes. Even after accounting for both individual and neighborhood SES factors, Black individuals continued to have increased severe exacerbation risk and persistently worse CT outcomes (emphysema, air trapping, and airway wall thickness). Disadvantages by individual- and neighborhood-level SES each partly explain disparities in respiratory outcomes between Black individuals and white individuals. Strategies to narrow the gap in SES disadvantages may help to reduce race-related health disparities in COPD; however, further work is needed to identify additional risk factors contributing to persistent disparities.
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http://dx.doi.org/10.1164/rccm.202002-0253OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048743PMC
April 2021

Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice.

Sci Transl Med 2020 08;12(557)

Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.

Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis.
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http://dx.doi.org/10.1126/scitranslmed.aay8798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976849PMC
August 2020

Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways.

J Allergy Clin Immunol 2021 03 11;147(3):894-909. Epub 2020 Aug 11.

Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz.

Background: The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium.

Objectives: We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program.

Methods: Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed.

Results: Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10 
Conclusions: By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity.
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http://dx.doi.org/10.1016/j.jaci.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876167PMC
March 2021

Increased airway iron parameters and risk for exacerbation in COPD: an analysis from SPIROMICS.

Sci Rep 2020 06 29;10(1):10562. Epub 2020 Jun 29.

Joan and Sanford I. Weill Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, USA.

Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195). BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV % predicted and exacerbation frequency. Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV % predicted as clinical covariates. BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers. BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively. Similar associations were not observed with plasma ferritin. Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals.
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http://dx.doi.org/10.1038/s41598-020-67047-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324559PMC
June 2020

Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2.

medRxiv 2020 May 19. Epub 2020 May 19.

Division of Infectious Diseases, University of California, San Francisco, CA, USA.

We studied the host transcriptional response to SARS-CoV-2 by performing metagenomic sequencing of upper airway samples in 238 patients with COVID-19, other viral or non-viral acute respiratory illnesses (ARIs). Compared to other viral ARIs, COVID-19 was characterized by a diminished innate immune response, with reduced expression of genes involved in toll-like receptor and interleukin signaling, chemokine binding, neutrophil degranulation and interactions with lymphoid cells. Patients with COVID-19 also exhibited significantly reduced proportions of neutrophils and macrophages, and increased proportions of goblet, dendritic and B-cells, compared to other viral ARIs. Using machine learning, we built 26-, 10- and 3-gene classifiers that differentiated COVID-19 from other acute respiratory illnesses with AUCs of 0.980, 0.950 and 0.871, respectively. Classifier performance was stable at low viral loads, suggesting utility in settings where direct detection of viral nucleic acid may be unsuccessful. Taken together, our results illuminate unique aspects of the host transcriptional response to SARS-CoV-2 in comparison to other respiratory viruses and demonstrate the feasibility of COVID-19 diagnostics based on patient gene expression.
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http://dx.doi.org/10.1101/2020.05.18.20105171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273244PMC
May 2020

Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis.

Int J Chron Obstruct Pulmon Dis 2019 20;14:2927-2938. Epub 2019 Dec 20.

Department of Medicine, University of Utah, Salt Lake City, UT, USA.

Objective: Bronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV (BDR) as a measure reflecting the change in flow and in FVC (BDR) reflecting the change in volume.

Methods: We analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.

Results: A majority of COPD participants exhibited BDR (52.7%). BDR occurred more often in earlier stages of COPD, while BDR occurred more frequently in more advanced disease. When defined by increases in either FEV or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDR was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDR was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV.

Conclusion: With advanced airflow obstruction in COPD, BDR is more prevalent in comparison to BDR and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV, BDR itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.

Clinical Trials Registration: ClinicalTrials.gov: NCT01969344T4.
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http://dx.doi.org/10.2147/COPD.S220164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930016PMC
July 2020

The role of genomic profiling in identifying molecular phenotypes in obstructive lung diseases.

Curr Opin Pulm Med 2020 01;26(1):84-89

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

Purpose Of Review: The biology underlying asthma and chronic obstructive pulmonary disease (COPD) is heterogeneous. Targeting therapies to patient subgroups, or 'molecular phenotypes', based on their underlying biology is emerging as an efficacious treatment strategy. This review summarizes the role of airway sample gene expression profiling in understanding molecular phenotypes in obstructive lung disease.

Recent Findings: Recent gene expression studies have reinforced the importance of Type two (T2) inflammation in asthma and COPD subgroups. Studies in asthma also suggest that the molecular phenotype with enhanced T2 inflammation is itself heterogeneous with a subgroup that has steroid-refractory inflammation. Other inflammatory pathways are also emerging as implicated in asthma and COPD molecular phenotypes, including Type one and Type 17 adaptive immune responses and proinflammatory cytokines, such as interleukin-6.

Summary: Genomic profiling studies are advancing our understanding of the complex biology contributing to asthma and COPD molecular phenotypes. Recent studies suggest that asthma and COPD subgroups may benefit from different treatment strategies than those currently in practice.
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http://dx.doi.org/10.1097/MCP.0000000000000646DOI Listing
January 2020

Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS.

Chest 2019 05 23;155(5):908-917. Epub 2019 Jan 23.

Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, San Francisco, CA.

Background: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma.

Methods: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV.

Results: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes.

Conclusions: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.
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http://dx.doi.org/10.1016/j.chest.2018.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533449PMC
May 2019

Safety and Tolerability of Comprehensive Research Bronchoscopy in Chronic Obstructive Pulmonary Disease. Results from the SPIROMICS Bronchoscopy Substudy.

Ann Am Thorac Soc 2019 04;16(4):439-446

4 Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan.

Rationale: There is an unmet need to investigate the lower airways in chronic obstructive pulmonary disease (COPD) to define pathogenesis and to identify potential markers to accelerate therapeutic development. Although bronchoscopy is well established to sample airways in various conditions, a comprehensive COPD research protocol has yet to be published.

Objectives: To evaluate the safety and tolerability of a comprehensive research bronchoscopy procedure suitable for multicenter trials and to identify factors associated with adverse events.

Methods: We report the detailed methodology used to conduct the bronchoscopy used in SPIROMICS (the Subpopulations and Intermediate Outcome Measures in COPD Study). The protocol entailed collection of tongue scrapings and oral rinses as well as bronchoscopy with airway inspection, bronchoalveolar lavage (BAL), protected brushings, and endobronchial biopsies. Visual airway characteristics were graded on a scale of 0 (normal appearance) to 3 (severe abnormality) in four domains: erythema, edema, secretions, and friability. Adverse events were defined as events requiring intervention. Logistic regression modeling assessed associations between adverse event occurrence and key variables.

Results: We enrolled 215 participants. They were 61 ± 9 years old, 71% were white, 53% were male, and post-bronchodilator forced expiratory volume in 1 second was 89 ± 19% predicted. Self-reported asthma was present in 22% of bronchoscopy participants. Oral samples were obtained in greater than or equal to 99% of participants. Airway characteristics were recorded in 99% and were most often characterized as free of edema (61.9%). Less than 50% reported secretions, friability, or erythema. BAL yielded 111 ± 57 ml (50%) of the 223 ± 65 ml of infusate, brushes were completed in 98%, and endobronchial biopsies were performed in 82% of procedures. Adverse events requiring intervention occurred in 14 (6.7%) of 208 bronchoscopies. In logistic regression models, female sex (risk ratio [RR], 1.10; 95% confidence interval [CI], 1.02-1.19), self-reported asthma (RR, 1.17; 95% CI, 1.02-1.34), bronchodilator reversibility (RR, 1.17; 95% CI, 1.04-1.32), COPD (RR, 1.10; 95% CI, 1.02-1.20), forced expiratory volume in 1 second (RR, 0.97; 95% CI, 0.95-0.99), and secretions (RR, 1.85; 1.08-3.16) or friability (RR, 1.64; 95% CI, 1.04-2.57) observed during bronchoscopy were associated with adverse events.

Conclusions: A research bronchoscopy procedure that includes oral sampling, BAL, endobronchial biopsy, and brushing can be safely performed. Airway characteristics during bronchoscopy, demographics, asthma or COPD, and lung function may convey increased risk for procedure-related events necessitating intervention.
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http://dx.doi.org/10.1513/AnnalsATS.201807-441OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441692PMC
April 2019

Heterogeneous burden of lung disease in smokers with borderline airflow obstruction.

Respir Res 2018 Nov 20;19(1):223. Epub 2018 Nov 20.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Utah, 26 N 1900 E, Salt Lake City, UT, 84132, USA.

Background: The identification of smoking-related lung disease in current and former smokers with normal FEV is complex, leading to debate regarding using a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV/FVC) of less than 0.70 versus the predicted lower limit of normal (LLN) for diagnosis of airflow obstruction. We hypothesized that the discordant group of ever-smokers with FEV/FVC between the LLN and 0.70 is heterogeneous, and aimed to characterize the burden of smoking-related lung disease in this group.

Methods: We compared spirometry, chest CT characteristics, and symptoms between 161 ever-smokers in the discordant group and 940 ever-smokers and 190 never-smokers with normal FEV and FEV/FVC > 0.70 in the SPIROMICS cohort. We also estimated sensitivity and specificity for diagnosing objective radiographic evidence of chronic obstructive pulmonary disease (COPD) using different FEV/FVC criteria thresholds.

Results: The discordant group had more CT defined emphysema and non-emphysematous gas trapping, lower post-bronchodilator FEV and FEF, and higher respiratory medication use compared with the other two groups. Within the discordant group, 44% had radiographic CT evidence of either emphysema or non-emphysematous gas trapping; an FEV/FVC threshold of 0.70 has greater sensitivity but lower specificity compared with LLN for identifying individuals with CT abnormality.

Conclusions: Ever-smokers with normal FEV and FEV/FVC <  0.70 but > LLN are a heterogeneous group that includes significant numbers of individuals with and without radiographic evidence of smoking-related lung disease. These findings emphasize the limitations of diagnosing COPD based on spirometric criteria alone.
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http://dx.doi.org/10.1186/s12931-018-0911-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245799PMC
November 2018

An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup.

J Clin Invest 2019 01 26;129(1):169-181. Epub 2018 Nov 26.

Department of Medicine, UCSF, San Francisco, California, USA.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar "molecular phenotypes" may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype.

Methods: We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids.

Results: The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation.

Conclusion: These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy.

Trial Registration: ClinicalTrials.gov NCT01969344.

Funding: Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C.
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http://dx.doi.org/10.1172/JCI121087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307967PMC
January 2019

Clinical Approach to the Therapy of Asthma-COPD Overlap.

Chest 2019 01 2;155(1):168-177. Epub 2018 Aug 2.

Department of Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY.

Over the last few years, there has been a renewed interest in patients with characteristics of both asthma and COPD. Although the precise definition of asthma-COPD overlap (ACO) is still controversial, patients with overlapping features are frequently encountered in clinical practice, and may indeed have worse clinical outcomes and increased health-care utilization than those with asthma or COPD. Therefore, there is a critical need to set a framework for the therapeutic approach of such patients. There are key distinctions in the therapy between asthma and COPD, particularly regarding the initial choice of therapy. However, there is considerable overlap in the use of existing medications for both diseases. Furthermore, novel therapies approved for asthma, such as monoclonal antibodies, may have a role in patients with COPD and ACO. The use of biomarkers, such as peripheral blood eosinophils, exhaled nitric oxide, and serum IgE, may help in selecting appropriate therapies for ACO. In this review, we provide an overview of available treatments for both asthma and COPD and explore their potential role in the treatment of patients with ACO.
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http://dx.doi.org/10.1016/j.chest.2018.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688980PMC
January 2019

Genome-wide association study of lung function and clinical implication in heavy smokers.

BMC Med Genet 2018 08 1;19(1):134. Epub 2018 Aug 1.

Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, BioScience Research Lab, Room 253, 1230 N. Cherry Avenue, PO Box 210242, Tucson, AZ, 85721, USA.

Background: The aim of this study is to identify genetic loci associated with post-bronchodilator FEV/FVC and FEV, and develop a multi-gene predictive model for lung function in COPD.

Methods: Genome-wide association study (GWAS) of post-bronchodilator FEV/FVC and FEV was performed in 1645 non-Hispanic White European descent smokers.

Results: A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV/FVC (p = 1.2 × 10) and FEV (p = 2.1 × 10). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10) and severity (OR = 4.1; p = 0.0036). Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype. 8.6% of the variance of post-bronchodilator FEV/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P <  2.2 × 10).

Conclusions: This study is the first to show genome-wide significant association of rs28929474 in SERPINA1 with lung function. Of clinical importance, heterozygotes of rs28929474 (4.7% of subjects) have significantly reduced pulmonary function, demonstrating a major impact in smokers. The multi-gene model is significantly associated with CT-based emphysema and clinical outcome measures of severity. Combining genetic information with demographic and environmental factors will further increase the predictive power for assessing reduced lung function and COPD severity.
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http://dx.doi.org/10.1186/s12881-018-0656-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090900PMC
August 2018

Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype.

J Clin Invest 2018 10 12;128(10):4343-4358. Epub 2018 Jul 12.

Department of Medicine.

GWAS have repeatedly mapped susceptibility loci for emphysema to genes that modify hedgehog signaling, but the functional relevance of hedgehog signaling to this morbid disease remains unclear. In the current study, we identified a broad population of mesenchymal cells in the adult murine lung receptive to hedgehog signaling, characterized by higher activation of hedgehog surrounding the proximal airway relative to the distal alveoli. Single-cell RNA-sequencing showed that the hedgehog-receptive mesenchyme is composed of mostly fibroblasts with distinct proximal and distal subsets with discrete identities. Ectopic hedgehog activation in the distal fibroblasts promoted expression of proximal fibroblast markers and loss of distal alveoli and airspace enlargement of over 20% compared with controls. We found that hedgehog suppressed mesenchymal-derived mitogens enriched in distal fibroblasts that regulate alveolar stem cell regeneration and airspace size. Finally, single-cell analysis of the human lung mesenchyme showed that segregated proximal-distal identity with preferential hedgehog activation in the proximal fibroblasts was conserved between mice and humans. In conclusion, we showed that differential hedgehog activation segregates mesenchymal identities of distinct fibroblast subsets and that disruption of fibroblast identity can alter the alveolar stem cell niche, leading to emphysematous changes in the murine lung.
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http://dx.doi.org/10.1172/JCI99435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159975PMC
October 2018

IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma.

Am J Respir Crit Care Med 2018 02;197(3):313-324

1 Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine.

Rationale: Quantification of type 2 inflammation provided a molecular basis for heterogeneity in asthma. Non-type 2 pathways that contribute to asthma pathogenesis are not well understood.

Objectives: To identify dysregulated pathways beyond type 2 inflammation.

Methods: We applied RNA sequencing to airway epithelial brushings obtained from subjects with stable mild asthma not on corticosteroids (n = 19) and healthy control subjects (n = 16). Sequencing reads were mapped to human and viral genomes. In the same cohort, and in a separate group with severe asthma (n = 301), we profiled blood gene expression with microarrays.

Measurements And Main Results: In airway brushings from mild asthma on inhaled corticosteroids, RNA sequencing yielded 1,379 differentially expressed genes (false discovery rate < 0.01). Pathway analysis revealed increased expression of type 2 markers, IFN-stimulated genes (ISGs), and endoplasmic reticulum (ER) stress-related genes. Airway epithelial ISG expression was not associated with type 2 inflammation in asthma or with viral transcripts but was associated with reduced lung function by FEV (ρ = -0.72; P = 0.0004). ER stress was confirmed by an increase in XBP1 (X-box binding protein 1) splicing in mild asthma and was associated with both type 2 inflammation and ISG expression. ISGs were also the most activated genes in blood cells in asthma and were correlated with airway ISG expression (ρ = 0.55; P = 0.030). High blood ISG expression in severe asthma was similarly unrelated to type 2 inflammation.

Conclusions: ISG activation is prominent in asthma, independent of viral transcripts, orthogonal to type 2 inflammation, and associated with distinct clinical features. ER stress is associated with both type 2 inflammation and ISG expression.
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http://dx.doi.org/10.1164/rccm.201706-1070OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811952PMC
February 2018
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