Respiratory Tract Diseases Commons^™

Blood Eosinophil Counts In Clinical Trials For Chronic Obstructive Pulmonary Disease, Dave Singh, Mona Bafadhel, Christopher E. Brightling, Frank C. Sciurba, Jeffrey L. Curtis, Fernando J. Martinez, Cara B. Pasquale, Debora D. Merrill, Norbert Metzdorf, Stefano Petruzzelli, Ruth Tal-Singer, Christopher Compton, Stephen I. Rennard, Ubaldo J. Martin

Journal Articles: Pulmonary & Critical Care Med

No abstract provided.

Heme Metabolism Genes Downregulated In Copd Cachexia, Ava C. Wilson, Preeti L. Kumar, Sool Lee, Margaret M. Parker, Itika Arora, Jarrett D. Morrow, Emiel F.M. Wouters, Richard Casaburi, Stephen I. Rennard, David A. Lomas, Alvar Agusti, Ruth Tal-Singer, Mark T. Dransfield, J. Michael Wells, Surya P. Bhatt, George Washko, Victor J. Thannickal, Hemant K. Tiwari, Craig P. Hersh, Peter J. Castaldi, Edwin K. Silverman, Merry-Lynn N. Mcdonald

Journal Articles: Pulmonary & Critical Care Med

INTRODUCTION: Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.

METHODS: We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (<  20 kg/m

RESULTS: The prevalence of …

Improving The Evaluation Of Copd Exacerbation Treatment Effects By Accounting For Early Treatment Discontinuations: A Post-Hoc Analysis Of Randomized Clinical Trials., Agnieszka Król, Robert Palmér, Virginie Rondeau, Stephen I. Rennard, Ulf G. Eriksson, Alexandra Jauhiainen

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. …

Agonist-Specific Desensitization Of Pge2-Stimulated Camp Signaling Due To Upregulated Phosphodiesterase Expression In Human Lung Fibroblasts, Francisco J. Nunez, Nancy Schulte, David M. Fogel, Joel Michalski, Stephen I. Rennard, Raymond B. Penn, Myron L. Toews, Rennolds S. Ostrom

Journal Articles: Pulmonary & Critical Care Med

Pulmonary fibrosis is characterized by fibroblasts persisting in an activated form, producing excessive fibrous material that destroys alveolar structure. The second messenger molecule cyclic 3',5'-adenosine monophosphate (cAMP) has antifibrotic properties, and prostaglandin E2 (PGE2) can stimulate cAMP production through prostaglandin E (EP)2 and EP4 receptors. Although EP receptors are attractive therapeutic targets, the effects of long-term exposure to PGE2 have not been characterized. To determine the effects of long-term exposure of lung fibroblasts to PGE2, human fetal lung (HFL)-1 cells were treated for 24 h with 100 nM PGE2 or other cAMP-elevating agents. cAMP levels stimulated by acute exposure to …

Hsp90 Inhibitors For Ipf/Covid-19, Ruben Manuel Luciano Colunga Biancatelli, Pavel A. Solopov, John Catravas

Bioelectrics Publications

Heat shock protein 90 (HSP90) is an important chaperone that assists the late stage folding of several proteins involved in cell survival in response to environmental stressors. The inhibition of HSP90 is followed by a complex modulation of the proteome and the kinome, that has proved beneficial in cancer and various neurodegenerative diseases. Additionally, accumulating literature suggests that HSP90 may be a key target during the development of pulmonary fibrosis and that its inhibition could serve as a new and exciting therapeutic approach. We have summarized the current evidence about HSP90’s role in Idiopathic Pulmonary Fibrosis (IPF), the results from …

Budesonide Enhances Agonist-Induced Bronchodilation In Human Small Airways By Increasing Camp Production In Airway Smooth Muscle, Cynthia J. Koziol-White, Timothy B. Johnstone, Maia L. Corpuz, Gaoyuan Cao, Sarah Orfanos, Vishal Parikh, Brian Deeney, Omar Tliba, Rennolds S. Ostrom, Ian Dainty, Reynold A. Panettieri Jr.

Pharmacy Faculty Articles and Research

The non-genomic mechanisms by which glucocorticoids modulate β₂ agonist-induced-bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E₂ (PGE₂), cholera toxin (CTX) or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE₂, or forskolin in the presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist-induced phosphorylation …

Transforming Growth Factor-Β1 Decreases Β2-Agonist–Induced Relaxation In Human Airway Smooth Muscle, Christie A. Ojiaku, Elena Chung, Vishal Parikh, Jazmean K. Williams, Anthony Schwab, Ana Lucia Fuentes, Maia L. Corpuz, Victoria Lui, Sam Paek, Natalia M. Bexiga, Shreya Narayan, Francisco J. Nunez, Kwangmi An, Rennolds S. Ostrom, Steven S. An, Reynold A. Pannettieri Jr.

Pharmacy Faculty Articles and Research

Helper T effector cytokines implicated in asthma modulate the contractility of human airway smooth muscle (HASM) cells. We have reported recently that a profibrotic cytokine, transforming growth factor (TGF)-β1, induces HASM cell shortening and airway hyperresponsiveness. Here, we assessed whether TGF-β1 affects the ability of HASM cells to relax in response to β₂-agonists, a mainstay treatment for airway hyperresponsiveness in asthma. Overnight TGF-β1 treatment significantly impaired isoproterenol (ISO)-induced relaxation of carbachol-stimulated, isolated HASM cells. This single-cell mechanical hyporesponsiveness to ISO was corroborated by sustained increases in myosin light chain phosphorylation. In TGF-β1–treated HASM cells, ISO evoked markedly lower …

Tgf-Β Induces A Heart Failure Phenotype Via Fibroblasts Exosome Signaling, Hesham Basma, Adelaide N. Johanson, Kajari Dhar, Daniel R. Anderson, Fang Qiu, Stephen I. Rennard, Brian D. Lowes

Journal Articles: Pulmonary & Critical Care Med

PURPOSE: The mechanisms for persistent and progressive loss of myocardial function in advanced heart failure (HF) remain incompletely characterized. In the current study, we sought to determine the impact of TGF-β on fibroblasts transcriptional profiles and assess if exosomes from TGF-β treated fibroblasts could induce a heart failure phenotype in co-cultured cardiomyocytes.

METHOD: Normal heart fibroblasts were treated with TGF-β with a final conc. of 2.5 ng/ml in serum free media. HF fibroblasts were also obtained from patients undergoing implantation of left ventricular assist devices. Exosomes were collected using three-step ultracentrifugation. Cardiomyocytes were co-cultured with exosomes from TGF-β-treated, HF and …

Bronchoalveolar Lavage Fluid From Copd Patients Reveals More Compounds Associated With Disease Than Matched Plasma, Eitan Halper-Stromberg, Lucas Gillenwater, Charmion Cruickshank-Quinn, Wanda Kay O'Neal, Nichole Reisdorph, Irina Petrache, Yonghua Zhuang, Wassim W. Labaki, Jeffrey L. Curtis, James Wells, Stephen I. Rennard, Katherine A. Pratte, Prescott Woodruff, Kathleen A. Stringer, Katerina Kechris, Russell P. Bowler

Journal Articles: Pulmonary & Critical Care Med

Smoking causes chronic obstructive pulmonary disease (COPD). Though recent studies identified a COPD metabolomic signature in blood, no large studies examine the metabolome in bronchoalveolar lavage (BAL) fluid, a more direct representation of lung cell metabolism. We performed untargeted liquid chromatography-mass spectrometry (LC-MS) on BAL and matched plasma from 115 subjects from the SPIROMICS cohort. Regression was performed with COPD phenotypes as the outcome and metabolites as the predictor, adjusted for clinical covariates and false discovery rate. Weighted gene co-expression network analysis (WGCNA) grouped metabolites into modules which were then associated with phenotypes. K-means clustering grouped similar subjects. We detected …

It's More Than Low Bmi: Prevalence Of Cachexia And Associated Mortality In Copd, Merry-Lynn N. Mcdonald, Emiel F.M. Wouters, Erica Rutten, Richard Casaburi, Stephen I. Rennard, David A. Lomas, Marcas Bamman, Bartolome Celli, Alvar Agusti, Ruth Tal-Singer, Craig P. Hersh, Mark Dransfield, Edwin K. Silverman

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Cachexia is associated with increased mortality risk among chronic obstructive pulmonary disease (COPD) patients. However, low body mass index (BMI) as opposed to cachexia is often used, particularly when calculating the BODE (BMI, Obstruction, Dyspnea and Exercise) index. For this reason, we examined mortality using a consensus definition and a weight-loss definition of cachexia among COPD cases and compared two new COPD severity indices with BODE.

METHODS: In the current report, the consensus definition for cachexia incorporated weight-loss > 5% in 12-months or low BMI in addition to 3/5 of decreased muscle strength, fatigue, anorexia, low FFMI and inflammation. The …

Prospective Observational Study In Patients With Obstructive Lung Disease: Novelty Design, Helen K. Reddel, Maria Gerhardsson De Verdier, Alvar Agustí, Gary Anderson, Richard Beasley, Elisabeth H. Bel, Christer Janson, Barry Make, Richard J. Martin, Ian Pavord, David Price, Christina Keen, Asparuh Gardev, Stephen I. Rennard, Alecka Sveréus, Aruna T. Bansal, Lance Brannman, Niklas Karlsson, Javier Nuevo, Fredrik Nyberg, Simon S. Young, Jørgen Vestbo

Journal Articles: Pulmonary & Critical Care Med

Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and share pathobiological mechanisms but are often considered distinct disorders. Prospective, observational studies across asthma, COPD and asthma-COPD overlap are limited. NOVELTY is a global, prospective observational 3-year study enrolling ∼12 000 patients ≥12 years of age from primary and specialist clinical practices in 19 countries (ClinicalTrials.gov identifier: NCT02760329). NOVELTY's primary objectives are to describe patient characteristics, treatment patterns and disease burden over time, and to identify phenotypes and molecular endotypes associated with differential outcomes over time in patients with a diagnosis/suspected diagnosis of asthma and/or COPD. NOVELTY …

Imaging-Based Clusters In Former Smokers Of The Copd Cohort Associate With Clinical Characteristics: The Subpopulations And Intermediate Outcome Measures In Copd Study (Spiromics), Babak Haghighi, Sanghun Choi, Jiwoong Choi, Eric A. Hoffman, Alejandro P. Comellas, John D. Newell, Chang Hyun Lee, R. Graham Barr, Eugene Bleecker, Christopher B. Cooper, David Couper, Mei Lan Han, Nadia N. Hansel, Richard E. Kanner, Ella A. Kazerooni, Eric A.C. Kleerup, Fernando J. Martinez, Wanda O'Neal, Robert Paine, Stephen I. Rennard, Benjamin M. Smith, Prescott G. Woodruff, Ching-Long Lin

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Quantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping.

METHODS: An imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, …

Patients' Perceptions And Patient-Reported Outcomes In Progressive-Fibrosing Interstitial Lung Diseases, Jeffrey J. Swigris, Kevin K. Brown, Rayid Abdulqawi, Ketan Buch, Daniel F. Dilling, Dirk Koschel, Krishna Thavarajah, Rade Tomic, Yoshikazu Inoue

Internal Medicine Faculty Publications

The effects of interstitial lung disease (ILD) create a significant burden on patients, unsettling almost every domain of their lives, disrupting their physical and emotional well-being and impairing their quality of life (QoL). Because many ILDs are incurable, and there are limited reliably-effective, life-prolonging treatment options available, the focus of many therapeutic interventions has been on improving or maintaining how patients with ILD feel and function, and by extension, their QoL. Such patient-centred outcomes are best assessed by patients themselves through tools that capture their perceptions, which inherently incorporate their values and judgements. These patient-reported outcome measures (PROs) can be …

Interfering With Dna Decondensation As A Strategy Against Mycobacteria, Enzo M. Scutigliani, Edwin R. Scholl, Anita E. Grootemaat, Sadhana Khanal, Jakub A. Kochan, Przemek M. Krawczyk, Eric A. Reits, Atefeh Garzan, Huy X. Ngo, Keith D. Green, Sylvie Garneau-Tsodikova, Jan M. Ruijter, Henk A. Van Veen, Nicole N. Van Der Wel

Pharmaceutical Sciences Faculty Publications

Tuberculosis is once again a major global threat, leading to more than 1 million deaths each year. Treatment options for tuberculosis patients are limited, expensive and characterized by severe side effects, especially in the case of multidrug-resistant forms. Uncovering novel vulnerabilities of the pathogen is crucial to generate new therapeutic strategies. Using high resolution microscopy techniques, we discovered one such vulnerability of Mycobacterium tuberculosis. We demonstrate that the DNA of M. tuberculosis can condense under stressful conditions such as starvation and antibiotic treatment. The DNA condensation is reversible and specific for viable bacteria. Based on these observations, we hypothesized …

Central Nervous System Histoplasmosis: Multicenter Retrospective Study On Clinical Features, Diagnostic Approach And Outcome Of Treatment, Joseph Wheat, Thein Myint, Ying Guo, Phebe Kemmer, Chadi A. Hage, Colin Terry, Marwan M. Azar, James Riddell, Peter Ender, Sharon Chen, Kareem Shehab, Kerry Cleveland, Eden Esguerra, James Johnson, Patty Wright, Vanja Douglas, Pascalis Vergidis, Winnie Ooi, John Baddley, David Bamberger, Raed N. Khairy, Holenarasipur R. Vikram, Elizabeth Jenny-Avital, Geetha Sivasubramanian, Karen Bowlware, Barbara Pahud, Juan Sarria, Townson Tsai, Maha Assi, Satish Mocherla

Internal Medicine Faculty Publications

Central nervous system (CNS) involvement occurs in 5 to 10% of individuals with disseminated histoplasmosis. Most experience has been derived from small single center case series, or case report literature reviews. Therefore, a larger study of central nervous system (CNS) histoplasmosis is needed in order to guide the approach to diagnosis, and treatment.

A convenience sample of 77 patients with histoplasmosis infection of the CNS was evaluated. Data was collected that focused on recognition of infection, diagnostic techniques, and outcomes of treatment.

Twenty nine percent of patients were not immunosuppressed. Histoplasma antigen, or anti-Histoplasma antibodies were detected in the …

The South Sudan: Tuberculosis, Blake Schwarz

Global Public Health

The South Sudan is a country that recently gained independence from the Sudan after a bloody twenty year civil war. They lost nearly two million lives during the war, and are now ravaged by Tuberculosis, or TB. After gaining their independence in 2011, the South Sudan has an average of 18,000 cases of TB at any time. This would consider TB in the South Sudan an endemic, as it always has a base level of TB cases that does not vary. There is medication for TB that is available to the citizens on the South Sudan, but the prescription is …

Imaging-Based Clusters In Current Smokers Of The Copd Cohort Associate With Clinical Characteristics: The Subpopulations And Intermediate Outcome Measures In Copd Study (Spiromics), Babak Haghighi, Sanghun Choi, Jiwoong Choi, Eric A. Hoffman, Alejandro P. Comellas, John D. Newell, R. Graham Barr, Eugene Bleecker, Christopher B. Cooper, David Couper, Mei Lan Han, Nadia N. Hansel, Richard E. Kanner, Ella A. Kazerooni, Eric A.C. Kleerup, Fernando J. Martinez, Wanda O'Neal, Stephen I. Rennard, Prescott G. Woodruff, Ching-Long Lin

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD.

METHODS: Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering.

RESULTS: Four clusters …

Use Of A 4-Week Up-Titration Regimen Of Roflumilast In Patients With Severe Copd, Henrik Watz, Nitin Bagul, Klaus F. Rabe, Stephen I. Rennard, Vijay Kt Alagappan, Jonas Román, Axel Facius, Peter Ma Calverley

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: The oral selective phosphodiesterase-4 inhibitor roflumilast (ROF) reduces exacerbations in patients with severe COPD. Adverse events (AEs) can cause early ROF discontinuation. Alternative dosing strategies may help patients continue their therapy.

METHODS: In this multicenter, double-blind trial, 1,321 patients with severe COPD were randomized 1:1:1 to 4 weeks' treatment with ROF 250 µg once daily (OD), 500 µg every other day (EOD), or 500 µg OD, each followed by ROF 500 µg OD for 8 weeks, plus standard therapy. The primary end point was the percentage of patients prematurely discontinuing study treatment.

RESULTS: Patients in the 250 µg OD/500 …

Centrilobular Emphysema And Coronary Artery Calcification: Mediation Analysis In The Spiromics Cohort, Surya P. Bhatt, Hrudaya P. Nath, Young-Il Kim, Rekha Ramachandran, Jubal R. Watts, Nina L.J. Terry, Sushil Sonavane, Swati P. Deshmane, Prescott G. Woodruff, Elizabeth C. Oelsner, Sandeep Bodduluri, Meilan K. Han, Wassim W. Labaki, J. Michael Wells, Fernando J. Martinez, R. Graham Barr, Mark T. Dransfield, Spiromics Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established.

METHODS: We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used …

Can Capture Be Used To Identify Undiagnosed Patients With Mild-To-Moderate Copd Likely To Benefit From Treatment?, Nancy K. Leidy, Fernando J. Martinez, Karen G. Malley, David M. Mannino, Meilan K. Han, Elizabeth D. Bacci, Randall W. Brown, Julia F. Houfek, Wassim W. Labaki, Barry J. Make, Catherine A. Meldrum, Wilson Quezada, Stephen I. Rennard, Byron Thomashow, Barbara P. Yawn

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE™) uses five questions and peak expiratory flow (PEF) thresholds (males ≤350 L/min; females ≤250 L/min) to identify patients with a forced expiratory volume in 1 second (FEV

METHODS: Data from the CAPTURE development study were used to test its sensitivity (SN) and specificity (SP) differentiating mild-to-moderate COPD (n=73) from no COPD (n=87). SN and SP for differentiating all COPD cases (mild to severe; n=259) from those without COPD (n=87) were also estimated. The modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT™) …

The Development Of Azd7624 For Prevention Of Exacerbations In Copd: A Randomized Controlled Trial, Naimish R. Patel, Danen M. Cunoosamy, Malin Fagerås, Ziad Taib, Sara Asimus, Tove Hegelund-Myrbäck, Sofia Lundin, Katerina Pardali, Nisha Kurian, Eva Ersdal, Cecilia Kristensson, Katarina Korsback, Robert Palmér, Mary N. Brown, Steven Greenaway, Leonard Siew, Graham W. Clarke, Stephen I. Rennard, Barry J. Make, Robert A. Wise, Paul Jansson

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.

OBJECTIVES: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.

METHODS: The p38 isoform most relevant to lung inflammation was assessed …

Variations In Practice Of Apnea Test For Brain Death: Review From A Multihospital Health Care System, Jeffrey Stein, Marvi V. Rijhwani, Ernesto Brauer

Journal of Patient-Centered Research and Reviews

Background: Ventilation encompasses both active and passive processes. Air is initially drawn into the lungs due to a negative intrathoracic pressure created using the respiratory muscles, most importantly the diaphragm. In contrast, expiration is the passive relaxation of the respiratory muscles. Oxygenation occurs when oxygen diffuses across the alveolar-capillary membrane. The ability to oxygenate without ventilation has been termed apneic diffusion oxygenation or apneic oxygenation. We believe it is crucial to keep alveoli open in order for adequate oxygenation to occur. This can be achieved with the aid of positive end-expiratory pressure (PEEP). We investigated this concept in patients who …

Hypersensitivity Of Vagal Pulmonary Afferents Induced By Tumor Necrosis Factor Alpha In Mice, Ruei-Lung Lin, Qihai Gu, Lu-Yuan Lee

Physiology Faculty Publications

Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFα also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFα caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFα on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFα (10 μg/ml, 0.03 ml) …

Cigarette Smoke Impairs A2a Adenosine Receptor Mediated Wound Repair Through Up-Regulation Of Duox-1 Expression., Zhi Tian, Hui Zhang, Jendayi Dixon, Nicole Traphagen, Todd A. Wyatt, Kusum K. Kharbanda, Samantha Simet, Narasaiah Kolliputi, Diane S Allen-Gipson

Journal Articles: Pulmonary & Critical Care Med

Cigarette smoke (CS) exposure and intrinsic factors such as the NADPH oxidases produce high levels of reactive oxygen species (ROS), ensuing inflammatory tissue injury. We previously demonstrated that CS-generated ROS, particularly hydrogen peroxide (H2O2), impaired adenosine stimulated wound repair. We hypothesized that CS exposure modulates expression of Dual oxidase 1 (Duox-1), a NADPH oxidases known to generate H2O2. To test this hypothesis, we used human bronchial epithelial cell line Nuli-1 and C57BL/6 mice. Cells were treated with 5% CS extract (CSE) for various periods of time, and mice were exposed to whole body CS for six weeks. Both CSE and …

Effect Of Low-Level Co2 On Innate Inflammatory Protein Response To Organic Dust From Swine Confinement Barns., David Schneberger, Jane M. Devasure, Kristina L. Bailey, Debra J. Romberger, Todd A. Wyatt

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Organic hog barn dust (HDE) exposure induces lung inflammation and long-term decreases in lung function in agricultural workers. While concentrations of common gasses in confined animal facilities are well characterized, few studies have been done addressing if exposure to elevated barn gasses impacts the lung immune response to organic dusts. Given the well documented effects of hypercapnia at much higher levels we hypothesized that CO2 at 8 h exposure limit levels (5000 ppm) could alter innate immune responses to HDE.

METHODS: Using a mouse model, C57BL/6 mice were nasally instilled with defined barn dust extracts and then housed in …

Effect Of Low-Level Co2 On Innate Inflammatory Protein Response To Organic Dust From Swine Confinement Barns., David Schneberger, Jane M. Devasure, Kristina L. Bailey, Debra J. Romberger, Todd A. Wyatt

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Organic hog barn dust (HDE) exposure induces lung inflammation and long-term decreases in lung function in agricultural workers. While concentrations of common gasses in confined animal facilities are well characterized, few studies have been done addressing if exposure to elevated barn gasses impacts the lung immune response to organic dusts. Given the well documented effects of hypercapnia at much higher levels we hypothesized that CO2 at 8 h exposure limit levels (5000 ppm) could alter innate immune responses to HDE.

METHODS: Using a mouse model, C57BL/6 mice were nasally instilled with defined barn dust extracts and then housed in …

Reduced Microrna-503 Expression Augments Lung Fibroblast Vegf Production In Chronic Obstructive Pulmonary Disease, Jun Ikari, Amy J. Nelson, Jannah Obaid, Alvaro Giron-Martinez, Kumiko Ikari, Fumihiko Makino, Shunichiro Iwasawa, Yoko Gunji, Maha Farid, Xingqi Wang, Hesham Basma, Dawn Demeo, Carol Feghali-Bostwick, Olaf Holz, Klaus Rabe, Xiangde Liu, Stephen I. Rennard

Journal Articles: Pulmonary & Critical Care Med

Alterations in microRNA (miRNA) expression may contribute to COPD pathogenesis. In COPD, lung fibroblast repair functions are altered in multiple ways, including extracellular mediator release. Our prior study revealed miR-503 expression is decreased in COPD lung fibroblasts, although the exact role played by miR-503 is undetermined. The current study examined a role of miR-503 in cytokine, growth factor and fibronectin production by lung fibroblasts from patients with and without COPD. Primary adult lung fibroblasts were isolated from patients with or without COPD. MiR-503 expression and interleukin (IL)-6, -8, PGE2, HGF, KGF, VEGF and fibronectin release were examined with or without …

Variability In Objective And Subjective Measures Affects Baseline Values In Studies Of Patients With Copd, Wayne H. Anderson, Jae Wook Ha, David J. Couper, Wanda K. O'Neal, R. Graham Barr, Eugene R. Bleecker, Elizabeth E. Carretta, Christopher B. Cooper, Claire M. Doerschuk, M. Bradley Drummond, Meilan K. Han, Nadia N. Hansel, Victor Kim, Eric C. Kleerup, Fernando J. Martinez, Stephen I. Rennard, Donald Tashkin, Prescott G. Woodruff, Robert Paine, Jeffrey L. Curtis, Richard W. Kanner, Spiromics Research Group

Journal Articles: Pulmonary & Critical Care Med

RATIONALE: Understanding the reliability and repeatability of clinical measurements used in the diagnosis, treatment and monitoring of disease progression is of critical importance across all disciplines of clinical practice and in clinical trials to assess therapeutic efficacy and safety.

OBJECTIVES: Our goal is to understand normal variability for assessing true changes in health status and to more accurately utilize this data to differentiate disease characteristics and outcomes.

METHODS: Our study is the first study designed entirely to establish the repeatability of a large number of instruments utilized for the clinical assessment of COPD in the same subjects over the same …

Body Mass Index Change In Gastrointestinal Cancer And Chronic Obstructive Pulmonary Disease Is Associated With Dedicator Of Cytokinesis 1, Merry-Lynn Noelle Mcdonald, Sungho Won, Manuel Mattheisen, Peter J. Castaldi, Michael H. Cho, Erica Rutten, Megan Hardin, Wai-Ki Yip, Stephen I. Rennard, David A. Lomas, Emiel F.M. Wouters, Alvar Agusti, Richard Casaburi, Christoph P. Lange, George O'Connor, Craig P. Hersh, Edwin K. Silverman

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: There have been a number of candidate gene association studies of cancer cachexia-related traits, but no genome-wide association study (GWAS) has been published to date. Cachexia presents in patients with a number of complex traits, including both cancer and COPD. The objective of the current investigation was to search for a shared genetic aetiology for change in body mass index (ΔBMI) among cancer and COPD by using GWAS data in the Framingham Heart Study.

METHODS: A linear mixed effects model accounting for age, sex, and change in smoking status was used to calculate ΔBMI in participants over 40 years …

Network-Based Analysis Reveals Novel Gene Signatures In Peripheral Blood Of Patients With Chronic Obstructive Pulmonary Disease, Ma'en Obeidat, Yunlong Nie, Virginia Chen, Casey P. Shannon, Anand Kumar Andiappan, Bernett Lee, Olaf Rotzschke, Peter J. Castaldi, Craig P. Hersh, Nick Fishbane, Raymond T. Ng, Bruce Mcmanus, Bruce E. Miller, Stephen I. Rennard, Peter D. Paré, Don D. Sin

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and there is a huge unmet clinical need to identify disease biomarkers in peripheral blood. Compared to gene level differential expression approaches to identify gene signatures, network analyses provide a biologically intuitive approach which leverages the co-expression patterns in the transcriptome to identify modules of co-expressed genes.

METHODS: A weighted gene co-expression network analysis (WGCNA) was applied to peripheral blood transcriptome from 238 COPD subjects to discover co-expressed gene modules. We then determined the relationship between these modules and forced expiratory volume in 1 s (FEV …