Important Chronic Obstructive Pulmonary Disease Research Articles

Molecular Mechanisms and the Interplay of Important Chronic Obstructive Pulmonary Disease Biomarkers Reveals Novel Therapeutic Targets.

Chronic Obstructive Pulmonary Disease (COPD) is a progressive, age-dependent, and unmet chronic inflammatory disease of the peripheral airways, leading to difficulty in exhalation. Several biomarkers have been tested in general towards the resolution for a long time, but no apparent success was achieved. Ongoing therapies of COPD have only symptomatic relief but no cure. Reactive oxygen species (ROS) are highly reactive species which include oxygen radicals and nonradical derivatives, and are the prominent players in COPD. They are produced as natural byproducts of cellular metabolism, but their levels can vary due to exposure to indoor air pollution, occupational pollution, and environmental pollutants such as cigarette smoke. In COPD, the lungs are continuously exposed to high levels of ROS thus leading to oxidative stress. ROS can cause damage to cells, proteins, lipids, and DNA which further contributes to the chronic inflammation in COPD and exacerbates the disease condition. Excessive ROS production can overwhelm cellular antioxidant systems and act as signaling molecules that regulate cellular processes, including antioxidant defense mechanisms involving glutathione and sirtuins which further leads to cellular apoptosis, cellular senescence, inflammation, and sarcopenia. In this review paper, we focused on COPD from different perspectives including potential markers and different cellular processes such as apoptosis, cellular senescence, inflammation, sirtuins, and sarcopenia, and tried to connect the dots between them so that novel therapeutic strategies to evaluate and target the possible underlying mechanisms in COPD could be explored.

The importance of chronic conditions for potentially avoidable hospitalizations among non-Hispanic Black and non-Hispanic White older adults in the US: a cross-sectional observational study

BackgroundNon-Hispanic (NH) Black older adults experience substantially higher rates of potentially avoidable hospitalization compared to NH White older adults. This study explores the top three chronic conditions preceding hospitalization and potentially avoidable hospitalization among NH White and NH Black Medicare beneficiaries in the United States.MethodsData on 4993 individuals (4,420 NH White and 573 NH Black individuals) aged ≥ 65 years from 2014 Medicare claims were linked with sociodemographic data from previous rounds of the Health and Retirement Study. Conditional inference random forests were used to rank the importance of chronic conditions in predicting hospitalization and potentially avoidable hospitalization separately for NH White and NH Black beneficiaries. Multivariable logistic regression with the top three chronic diseases for each outcome adjusted for sociodemographic characteristics were conducted to quantify the associations.ResultsIn total, 22.1% of NH White and 24.9% of NH Black beneficiaries had at least one hospitalization during 2014. Among those with hospitalization, 21.3% of NH White and 29.6% of NH Black beneficiaries experienced at least one potentially avoidable hospitalization. For hospitalizations, chronic kidney disease, heart failure, and atrial fibrillation were the top three contributors among NH White beneficiaries and acute myocardial infarction, chronic obstructive pulmonary disease (COPD), and chronic kidney disease were the top three contributors among NH Black beneficiaries. These chronic conditions were associated with increased odds of hospitalization for both groups. For potentially avoidable hospitalizations, asthma, COPD, and heart failure were the top three contributors among NH White beneficiaries and fibromyalgia/chronic pain/fatigue, COPD, and asthma were the top three contributors among NH Black beneficiaries. COPD and heart failure were associated with increased odds of potentially avoidable hospitalization among NH White beneficiaries, whereas only COPD was associated with increased odds of potentially avoidable hospitalizations among NH Black beneficiaries.ConclusionHaving at least one hospitalization and at least one potentially avoidable hospitalization was more prevalent among NH Black than NH White Medicare beneficiaries. This suggests greater opportunity for increasing prevention efforts among NH Black beneficiaries. The importance of COPD for potentially avoidable hospitalizations further highlights the need to focus on prevention of exacerbations for patients with COPD, possibly through greater access to primary care and continuity of care.

Occupational exposures and incidence of chronic bronchitis and related symptoms over two decades: the European Community Respiratory Health Survey

ObjectivesChronic bronchitis (CB) is an important chronic obstructive pulmonary disease (COPD)-related phenotype, with distinct clinical features and prognostic implications. Occupational exposures have been previously associated with increased risk of CB...

Exhaustion of Airway Basal Progenitor Cells in Early and Established Chronic Obstructive Pulmonary Disease.

Up to 40% of smokers develop chronic obstructive pulmonary disease (COPD) over a period that spans decades. Despite the importance of COPD, much remains to be learned about susceptibility and pathogenesis, especially during early, prediagnostic stages of disease. Airway basal progenitor cells are crucial for lung health and resilience because of their ability to repair injured airways. In COPD, the normal airway epithelium is replaced with increased basal and secretory (mucous) cells and decreased ciliated cells, suggesting that progenitors are impaired. To examine airway basal progenitor cells and lung function in smokers with and without COPD. Bronchial biopsies taken from smokers at risk for COPD and lung cancer were used to acquire airway basal progenitor cells. They were evaluated for count, self-renewal, and multipotentiality (ability to differentiate to basal, mucous, and ciliated cells), and progenitor count was examined for its relationship with lung function. Basal progenitor count, self-renewal, and multipotentiality were all reduced in COPD versus non-COPD. COPD progenitors produced an epithelium with increased basal and mucous cells and decreased ciliated cells, replicating the COPD phenotype. Progenitor depletion correlated with lung function and identified a subset of subjects without COPD with lung function that was midway between non-COPD with high progenitor counts and those with COPD. Basal progenitor dysfunction relates to the histologic and physiologic manifestations of COPD and identifies a subset that may represent an early, prediagnostic stage of COPD, indicating that progenitor exhaustion is involved in COPD pathogenesis.

The prevalence of chronic obstructive pulmonary disease in hookah smokers.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Hookah smoking is growing worldwide and particularly in Iran. The aim of this study was to determine the prevalence of obstructive pulmonary dysfunction in hookah smokers. We conducted a population-based study in Bushehr Province, Iran. A total of 245 subjects aged 35 years or older who were taking hookah for at least 15 years and 245 healthy controls were enrolled in the study and spirometry was done. Statistical analyses were performed using SPSS for windows software version 19. The prevalence of COPD among the exposed group of hookah smoke was 10.2%, with the rate being significantly higher in the patients with older age (p < 0.001), duration of hookah smoking (p < 0.001), men (p = 0.026), ≥3 hookahs/day (p = 0.006), history of cough for ≥2 years (p = 0.002), in patients with a history of sputum for ≥2 years (p = 0.031), and in patients with a history of dyspnea for ≥2 years (p = 0.001). The results of the logistic regression analysis demonstrated that older age, male gender, smoking, and occupational exposure were independent predictive factors for COPD. The results of our study suggest that hookah smoking significantly increases the risk of COPD. Given the importance of COPD in the global burden of diseases, it is necessary to carry out further studies on the relationship between hookah use and COPD.

New insights in chronic obstructive pulmonary disease and comorbidity.

Interest in cognitive impairment in patients with chronic obstructive pulmonary disease (COPD) was raised long ago (2). Yet, it has not been investigated extensively whether COPD is a risk factor for any mild cognitive impairment (MCI), the earliest symptomatic phase of dementia. Singh and colleagues (1) conducted a prospective, population-based study to examine whether diagnosis and duration of COPD are associated with an increased risk for incident MCI and MCI subtypes (amnestic MCI [A-MCI] and nonamnestic MCI [NA-MCI]). A total of 1,425 cognitively normal individuals, including individuals with a medical record–based diagnosis of COPD (n = 171), aged 70 to 89 years, underwent assessment with a nurse interview (including questions about memory and the Clinical Dementia Rating Scale), neurologic examination (including the Short Test of Mental Status and the Unified Parkinson’s Disease Rating Scale), and neuropsychological testing (including nine cognitive tests to assess the cognitive domains of memory, language, executive function, and visuospatial skills) at baseline and every 15 months thereafter. Normal cognition, MCI, or dementia was diagnosed according to published criteria and was based on a consensus agreement among the multidisciplinary staff, taking into account all the information collected. MCI cases were classified into A-MCI or NA-MCI, depending on whether the memory domain was impaired. Three hundred seventy out of 1,425 patients developed incident MCI, of whom 230 (62.2%) had A-MCI, 97 (26.2%) NA-MCI, 27 (7.3%) MCI of unknown type, and 16 (4.3%) progressed from normal cognition at one visit to having dementia at the next. The median duration of follow-up was 5.1 years. After adjusting for covariates, a diagnosis of COPD significantly increased the risk for NA-MCI by 83% but not of any MCI or A-MCI in multivariate analyses. A dose–response relationship was found, such that individuals with COPD duration of longer than 5 years at baseline had the greatest risk for any MCI and NA-MCI. The current study is limited by its lack of data on spirometry and data on smoking duration. In summary, MCI, and particularly NA-MCI, is increased in individuals diagnosed with COPD, and a dose–response relationship was found with the duration of COPD. These findings stress the importance of COPD as a risk factor for MCI and may provide a substrate for early intervention or to treat COPD more aggressively at earlier points to prevent or delay the onset and progression of MCI. n

Dectin-1 Is Expressed in Human Lung and Mediates the Proinflammatory Immune Response to Nontypeable Haemophilus influenzae

The C-type lectin receptor Dectin-1 is expressed mainly on myeloid cells mediating the immune response targeting respiratory pathogens such as Aspergillus fumigatus and Mycobacterium tuberculosis. The pulmonary epithelium serves as an important interface for interactions between these pathogens and the respiratory tract. Therefore, we analyzed the expression pattern of Dectin-1 in the human lung. Immunohistochemically stained human lung sections from 17 out of 19 individuals were positive for Dectin-1, which was expressed mainly apically on bronchial and alveolar epithelium. Our results showed no correlation with chronic obstructive pulmonary disease (COPD) or the smoking habits of the patients. Nontypeable Haemophilus influenzae (NTHI), an important bacterial pathogen of the respiratory tract with significant importance in COPD, has also been proposed to be recognized by Dectin-1, suggesting a possible impact on the NTHI-dependent immune response in human airways. Therefore, the involvement of Dectin-1 in NTHI-triggered cytokine responses was investigated in primary normal human bronchial epithelial (NHBE) cells and in the A549 cell line stably transfected with Dectin-1. The presence of Dectin-1 significantly increased cytokine release in response to NTHI in NHBE and A549 cells. In addition, phosphorylation of the Dectin-1 hem-immunoreceptor tyrosine-based activation motif (hemITAM) was essential for the Dectin-1-triggered response to NTHI in A549 cells. In conclusion, in human airways, epithelium-expressed Dectin-1 may play a significant role in generating an NTHI-mediated, proinflammatory immune response.

Dectin-1 is expressed in human lung and mediates the proinflammatory immune response to nontypeable Haemophilus influenzae.

ABSTRACTThe C-type lectin receptor Dectin-1 is expressed mainly on myeloid cells mediating the immune response targeting respiratory pathogens such as Aspergillus fumigatus and Mycobacterium tuberculosis. The pulmonary epithelium serves as an important interface for interactions between these pathogens and the respiratory tract. Therefore, we analyzed the expression pattern of Dectin-1 in the human lung. Immunohistochemically stained human lung sections from 17 out of 19 individuals were positive for Dectin-1, which was expressed mainly apically on bronchial and alveolar epithelium. Our results showed no correlation with chronic obstructive pulmonary disease (COPD) or the smoking habits of the patients. Nontypeable Haemophilus influenzae (NTHI), an important bacterial pathogen of the respiratory tract with significant importance in COPD, has also been proposed to be recognized by Dectin-1, suggesting a possible impact on the NTHI-dependent immune response in human airways. Therefore, the involvement of Dectin-1 in NTHI-triggered cytokine responses was investigated in primary normal human bronchial epithelial (NHBE) cells and in the A549 cell line stably transfected with Dectin-1. The presence of Dectin-1 significantly increased cytokine release in response to NTHI in NHBE and A549 cells. In addition, phosphorylation of the Dectin-1 hem-immunoreceptor tyrosine-based activation motif (hemITAM) was essential for the Dectin-1-triggered response to NTHI in A549 cells. In conclusion, in human airways, epithelium-expressed Dectin-1 may play a significant role in generating an NTHI-mediated, proinflammatory immune response.

Genome‐wide association studies identify locus on 6p21 influencing lung function in the Korean population

Loss of lung function is an important chronic obstructive pulmonary disease phenotype and decreased forced expiratory volume in 1 s (FEV₁) is an independent risk factor of morbidity and mortality. Genome-wide association studies (GWAS) identifying genetic variants underlying lung function have been performed mostly in Caucasian populations. In this study, we aimed to identify genetic variants influencing lung function in a Korean population. GWAS on lung function (FEV₁ and FEV₁/forced vital capacity (FVC) ratio) were performed in two cohort studies. A population-based cohort, the Korean Association Resource phase 3 (KARE3) (6223 subjects), served as a discovery set. The replication analysis was performed in a family-based cohort, the Healthy Twin Study (HTS; 2730 subjects). Dense single-nucleotide polymorphism array data from each study were imputed and used for genetic analysis. At the discovery phase, variants in 6p21 and 17q24 showed the strongest association with FEV₁/FVC ratio and FEV₁. Several variants in FAM13A on 4q22 locus exhibited positive association with FEV₁/FVC ratio. In the replication set, PPT2 in the 6p21 region showed significant association with lung function in the HTS, although the 4q22 locus and the 17q24 locus were not replicated. We identified that PPT2 on chromosome 6p21 is associated with loss of lung function in the Korean population.

Skeletal muscle dysfunction in COPD: clinical and laboratory observations

COPD (chronic obstructive pulmonary disease), although primarily a disease of the lungs, exhibits secondary systemic manifestations. The skeletal muscles are of particular interest because their function (or dysfunction) not only influences the symptoms that limit exercise, but may contribute directly to poor exercise performance. Furthermore, skeletal muscle weakness is of great clinical importance in COPD as it is recognized to contribute independently to poor health status, increased healthcare utilization and even mortality. The present review describes the current knowledge of the structural and functional abnormalities of skeletal muscles in COPD and the possible aetiological factors. Increasing knowledge of the molecular pathways of muscle wasting will lead to the development of new therapeutic agents and strategies to combat COPD muscle dysfunction.

Interpreting Results from Clinical Trials: Understanding Minimal Clinically Important Differences in COPD Outcomes

This issue of the COPD: Journal of Chronic Obstructive Pulmonary Disease presents the papers from the “Workshop on Minimal Clinically Important Differences in COPD” held in Bal Harbour, Florida, on January 11–13, 2004. The goals of this meeting were to: discuss the significance of and methodology for determining minimal clinically important differences (MCID) in health outcomes of importance in chronic obstructive pulmonary disease (COPD); review the current knowledge about MCID in outcomes of importance, including dyspnea, quality of life, exercise performance, and pulmonary function, in the management of patients with COPD; apply methodologies to determine MCID using existing data for outcomes of importance in COPD; and develop recommendations for further studies to determine MCID in health outcomes of importance in COPD.

Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study

Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease. We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV(1)] 46.8% of predicted, FEV(1)/forced vital capacity [FVC] 54.6%, and postsalbutamol reversibility 5.4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV(1) before and after use of a bronchodilator. Analyses were by intention to treat. Cilomilast 15 mg twice daily significantly improved FEV(1) compared with placebo (mean 130 mL vs -30 mL [95% CI 90-240] at week 6, p<0.0001). FVC and peak expiratory flow were also improved (p=0.001 and p<0.0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups. Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.