Candidate genes controlling pulmonary function in mice: transcript profiling and predicted protein structure

In this retrospective study of 97 male workers exposed to asbestos for 2-50 yr, data were collected on chest x-ray findings and lung function, including lung volumes, forced expiratory flow rates (i.e., forced expiratory volume in 1 sec [FEV1.0], forced expiratory flow measured between 25% and 75% of forced vital capacity [FEF(25-75%)]), airway resistance (R(aw)), carbon monoxide (CO)-diffusing capacity, and the existence of airway obstruction reversible by a beta-adrenergic agonist (RAO). The authors performed multiple-regression analyses to correlate the variations in lung function data with age, smoking habits, duration of asbestos exposure, and time since last exposure. Occupational activities of subjects that might induce specific lung abnormalities were also considered. No significant decrease was seen in lung volumes or CO-diffusing capacity; however, a decrease in FEV1.0 and an increase in R(aw) were measured in 65% of the subjects, and an isolated decrease in FEF(25-75%) occurred in only 18%. There was no difference in lung-function data between subjects who had chest x-ray signs of abnormalities (n = 59) and those who did not (n = 38). A significant relationship was found between the decrease in FEV1.0 and age; however, no correlation was noted between altered lung function and cigarette smoking, duration of asbestos exposure, or time since last exposure. RAO prevalence was higher (34%) than previously reported (9%) in subjects with chronic obstructive pulmonary disease (COPD) who were not exposed to asbestos or outdoor pollution. The RAO prevalence in asbestos-exposed workers was nearly the same as that measured in COPD subjects who lived downtown and who were exposed to outdoor pollution (36%). The high RAO prevalence in asbestos-exposed workers was found in 43% of subjects who were exposed only to asbestos, and in 33% of subjects who were also exposed to air pollution due to their occupational activities. It is hoped that the observations in this study will encourage practitioners to check for RAO in asbestos workers who use inhaled bronchodilators.

The prevalence of small airway dysfunction (SAD) in patients with chronic obstructive pulmonary disease (COPD) across different ethnicities is poorly understood. This study aimed to estimate the prevalence of SAD in stable COPD patients. We conducted a cross-sectional study of 196 consecutive stable COPD patients. We measured pre- and post-bronchodilator (BD) lung function and respiratory impedance. The severity of COPD and lung function abnormalities was graded in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. SAD was defined as either difference in whole-breath resistance at 5 and 19 Hz > upper limit of normal or respiratory system reactance at 5 Hz < lower limit of normal. The cohort consisted of 95.9% men, with an average age of 66.3 years. The mean forced expiratory volume 1 second (FEV1) % predicted was 56.4%. The median COPD assessment test (CAT) scores were 14. The prevalence of post-BD SAD across the GOLD grades 1 to 4 was 14.3%, 51.1%, 91%, and 100%, respectively. The post-BD SAD and expiratory flow limitation at tidal breath (EFLT) were present in 62.8% (95% confidence interval [CI], 56.1 to 69.9) and 28.1% (95% CI, 21.9 to 34.2), respectively. COPD patients with SAD had higher CAT scores (15.5 vs. 12.8, p<0.01); poor lung function (FEV1% predicted 46.6% vs. 72.8%, p<0.01); lower diffusion capacity for CO (4.8 mmol/min/kPa vs. 5.6 mmol/min/kPa, p<0.01); hyperinflation (ratio of residual volume to total lung capacity % predicted: 159.7% vs. 129%, p<0.01), and shorter 6-minute walk distance (367.5 m vs. 390 m, p=0.02). SAD is present across all severities of COPD. The prevalence of SAD increases with disease severity. SAD is associated with poor lung function and higher symptom burden. Severe SAD is indicated by the presence of EFLT.

BackgroundIn patients with chronic obstructive pulmonary disease (COPD), the independent contributions of individual lung function variables to outcomes may be lower when they are modelled together if they are collinear. In addition, lung volume measurements may not be necessary after spirometry data have been obtained. However, these hypotheses depend on whether forced vital capacity (FVC) can predict total lung capacity (TLC). Moreover, the definitions of hyperinflation and air trapping according to lung function variables overlap and need be clarified. Therefore, the aim of this study was to evaluate the relationships among various lung function parameters to elucidate these issues.MethodsDemographic data and 26 parameters of full lung function were measured in 94 men with COPD and analyzed using factor and correlation analyses.ResultsFactor analysis revealed five latent factors. Inspiratory capacity (IC)/TLC and residual volume (RV)/TLC were most strongly correlated with all other lung volumes. IC/TLC, RV/TLC, and functional residual capacity (FRC)/TLC were collinear and were potential markers of air trapping, whereas TLC%, FRC%, and RV% were collinear and were potential markers of hyperinflation. RV/TLC >0.4 (or IC/TLC <0.4) was comparable with the ratio of forced expiratory volume in one second (FEV1) and FVC <0.7. FVC% and FEV1% were poorly correlated with TLC%. The correlation study showed that TLC%, RV/TLC, and FEV1% could be used to represent individual latent factors for hyperinflation, air trapping, inspiration, expiration, and obstruction. Combined with diffusion capacity%, these four factors could be used to represent comprehensive lung function.ConclusionsThis study identified collinear relationships among individual lung function variables and thus selecting variables with close relationships for correlation studies should be performed with caution. This study also differentiated variables for air trapping and lung hyperinflation. Lung volume measurements are still required even when spirometry data are available. Four out of 26 lung function variables from individual latent factors could be used to concisely represent lung function.

Pulmonary hemodynamics and lung function in patients with COPD and DPLD

Muscone, a key component of musk, exhibits anti-inflammatory properties. However, its therapeutic potential in inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), remains largely unexplored. This study aimed to investigate whether Muscone could exert a protective effect in a mouse model of COPD in vivo. A COPD animal model was established by exposing mice to cigarette smoke (CS) and administering lipopolysaccharide (LPS) intranasally. After 4 weeks, mice were treated daily with dexamethasone (DEX) or different doses of Muscone for 3 weeks. Mouse body weight, lung function, and histopathology were determined. Serum levels of cytokines (IL-38, IL-1β, IL-17, TGF-β, IFN-γ) were measured using ELISA and qRT-PCR. Lung expression of CXCR3, IFN-γ, IL-17A, and RORγt was assessed by immunofluorescence. The body weight of COPD mice was significantly lower than that of Muscone-treated COPD mice, consistent with decreased lung function, accompanied by reduced circulating and lung IL-38 levels. After Muscone administration, lung function was significantly improved, accompanied by upregulation of circulating and lung anti-inflammatory cytokines, including IL-38, in a dose-dependent manner, while the expression of pro-inflammatory cytokines was significantly reduced. Additionally, Muscone significantly inhibited the protein expression of CXCR3, IFN-γ, IL-17A, and RORγt in lung tissues of COPD mice. This study demonstrates that Muscone improves lung function in mice with COPD, potentially through a mechanism that may involve the modulation of cytokine expression, including the potential upregulation of anti-inflammatory cytokines such as IL-38. The precise underlying mechanisms of Muscone's therapeutic effects in COPD remain to be fully elucidated. Further research is needed to investigate the correlation between COPD lung pathophysiology and the specific effects of Muscone treatment, including a more detailed analysis of the balance between pro- and anti-inflammatory mediators in COPD animal models, particularly utilizing IL-38 GKO mice to further investigate the role of IL-38 in mediating the therapeutic effects of Muscone.

Collapsibility of Lung Volume by Paired Inspiratory and Expiratory CT Scans: Correlations with Lung Function and Mean Lung Density

Bone morphogenetic protein 6 (BMP-6) modulates lung function, pulmonary iron levels and cigarette smoke-induced inflammation.

The aim of this study was to evaluate the effects of aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia (PCP) on lung function. Nine consecutive HIV-positive patients, who inhaled pentamidine as primary prophylaxis against PCP, were studied monthly by means of lung function tests over a period of nine months (Group 1). Eleven patients receiving primary PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX) (Group 2) were compared to Group 1. Lung function testing consisted of vital lung capacity (VC), total lung capacity (TLC), airway resistance (Raw), forced expiratory volume (FeV1), and CO-diffusion capacity (DLCO). We compared the results of lung function testing measured prior to inhalation of pentamidine to those three, six, and nine months after starting the pro-phylactic treatment within the two groups and between them. The results of this study showed that aerosolized pentamidine does not influence lung function; the data did not differ significantly either at month zero, three, six, and nine or between the two groups. This study suggests that aerosolized pentamidine has no effect on lung function during long-term administration.

Targeted Deletion of Jun/AP-1 in Alveolar Epithelial Cells Causes Progressive Emphysema and Worsens Cigarette Smoke–Induced Lung Inflammation

UK COPD treatment: failing to progress

Introduction Chronic obstructive pulmonary disease (COPD) is a common worldwide problem associated with morbidity and mortality that, unlike other diseases, is increasing. Recently, COPD has become the third leading cause of death in the United States, an event that was not predicted to occur until the year 2020. Therapy for COPD focuses on smoking cessation, bronchodilators, oxygen therapy, pulmonary rehabilitation, lung volume reduction surgery (LVRS), transplantation and treatment of comorbidities. While many of these interventions may improve dyspnea and quality of life, only oxygen supplementation in those with hypoxemia at rest, smoking cessation and LVRS have been associated with improved mortality in COPD. This chapter will review the role of LVRS in the treatment of patients with advanced COPD, and also examine the current status of minimally invasive bronchoscopic techniques for lung reduction that are approved overseas but are currently under study in the United States. Rationale for lung reduction in COPD COPD is an inflammatory disease that leads to airflow obstruction secondary to a combination of airway disease and emphysema, primarily in the distal small airways of the lung. The small airways become narrowed due to airway inflammation, smooth muscle hypertrophy, peribronchial fibrosis and mucus plugging. In emphysema, the destruction of alveolar walls leads to a loss of tethering of distal small airways, predisposing the airway to expiratory collapse. Most individuals with COPD will have a mixture of small airways obstruction and emphysema, but some will have a predominance of one abnormality or the other. Lung emptying is determined by the expiratory time constant, which is the product of airway resistance and lung compliance. Because subjects with emphysema have both increased lung compliance and airways resistance, they have impaired lung emptying and are prone to hyperinflation. As emphysema progresses, total lung capacity (TLC) and residual volume (RV) both increase as a result of decreased lung compliance and unopposed chest wall recoil causing hyperinflation and gas trapping, respectively. During exertion, the respiratory rate increases, reducing the time available for lung emptying, and the end-expiratory lung volume (EELV) rises even further, leading to dynamic hyperinflation. Figure 8.1 demonstrates the rise in lung volumes that occurs during exercise in severe COPD. EELV rises during exercise, thereby limiting the normal increase in tidal volume that occurs during exercise.

Traditionally, the assessment of airflow limitation and acute reversibility in response to inhaled bronchodilator relies on spirometry, particularly the forced expiratory volume in 1 s (FEV1). This variable is usually the primary outcome measure for clinical trials in patients with chronic obstructive pulmonary disease (COPD) since it is a simple, reproducible and inexpensive measurement [1]. There are limitations, however, to the use of FEV1 as an endpoint in studies to asses the effect of bronchodilator drugs in COPD patients. For instances, measurement of FEV1 requires a deep inhalation manoeuvre which may alter airway calibre [2]. Furthermore, FEV1 correlates weakly with exercise capacity and dyspnoea, and changes in FEV1 following bronchodilator therapy are poorly predictive of improved symptoms and exercise endurance [3]. Thus, exclusive reliance on the change in FEV1 as the primary outcome measure in assessing therapeutic efficacy can lead to underestimation of a true clinical benefit in patient with COPD. Body plethysmography is a well-established technique that allows also for the measurement of airway resistance and conductance, and is widely used in the assessment of bronchodilator efficacy in patients with COPD [4]. The impulse oscillation system (IOS) has been introduced as a user-friendly commercial version of the forced oscillation technique that provides a frequency-integrated measurement of total respiratory resistance and reactance [5]. Both these techniques do not require forced expiratory manoeuvres and are more sensitive than FEV1 for measuring the bronchodilator response in both healthy subjects [6] and patients with asthma [7]. In this issue of the Journal, Borril et al. [8] have investigated the variability and sensitivity to bronchodilation of spirometry, IOS and body plethysmography in patients with COPD. They found that, although spirometry is more reproducible than IOS and body plethysmography, total respiratory resistance and reactance measured at the lower frequency range (5 Hz) by means of IOS, as well as plethysmographic airway resistance and conductance, are more sensitive than lung volumes and forced expiratory flows in detecting minimal bronchodilation following salbutamol administration. The results of the study are interesting and rise the question of the importance of the use of IOS and body plethysmography, rather than spirometry, in the evaluation of the bronchodilator response in COPD patients. Some issues need to be taken into consideration when comparing the bronchodilator response measured by different lung function tests. It has been shown that the sensitivity to bronchodilation of different lung function tests depends on the method used to quantify the response [9]. When changes in lung function are expressed as percent of baseline, as is the case of the study by Borril et [8], respiratory resistance appears to be the most sensitive test, while, in contrast, spirometry is more sensitive when absolute changes are considered [9]. Furthermore, the cut-off level for a positive bronchodilator response, which is usually selected on the basis of the intraindividual coefficients of variation for a given lung function test, affects the sensitivity to bronchodilation of lung function tests [9]. Bronchodilation causes smaller changes in the values of spirometry than of respiratory resistances, but also the variability and, consequently, the cut-off level for a positive response is smaller for the former. Thus, it is unlikely that a single lung function test can be use to quantify the bronchodilator response. Although IOS and body plethysmography are practical methods for quantifying respiratory mechanics especially in noncooperative patients, measurements obtained with these lung function techniques cannot be interchangeable with those of spirometry. Further studies are needed to establish the actual clinical utility of IOS, particularly its relationship with exercise capacity and symptoms, in patients with COPD. It is my opinion that, for a comprehensive therapeutic evaluation of bronchodilator therapy in patients with COPD, IOS is unlikely to obviate the need for measurements of lung hyperinflation, symptoms intensity and exercise endurance. The future development of a composite index that collectively incorporates these outcome measures may increase our ability to critically evaluate the clinical benefit of bronchodilator therapy in patients with COPD.

Spirometry based measurement of lung function is a global initiative for chronic obstructive lung disease (GOLD) standard to diagnose chronic obstructive pulmonary disease (COPD), one of the leading causes of mortality worldwide. The environmental and behavioural risk factors for COPD includes tobacco smoking, air pollutants and biomass fuel exposure, which can induce one or more abnormal lung function patterns. While smoking remains the primary risk factor, only 15-20% smokers develop COPD, indicating that the genetic factors are also likely to play a role. According to the study of Global Burden of Disease 2015, ∼174 million people across the world have COPD. From a comprehensive literature search conducted using the 'PubMed' and 'GWAS Catalogue' databases, and reviewing the literature available, only a limited number of studies were identified which had attempted to investigate the genetics of COPD and lung volumes, implying a huge research gap. With the advent of genomewide association studies several genetic variants linked to lung function and COPD, like HHIP, HTR4, ADAM19 and GSTCD etc., have been found and validated in different population groups, suggesting their potential role in determining lung volume and risk for COPD. This article aims at reviewing the present knowledge of the genetics of lung function and COPD.

Now lung volume reduction surgery (LVRS) has become one of the most effective methods for the management of some cases of severe chronic obstructive pulmonary disease (COPD). We evaluated the mid-term effects of LVRS on pulmonary function in patients with severe COPD. Ten male patients with severe COPD aged 38 - 70 years underwent LVRS and their pulmonary function was assessed before, 3 months and 3 years after surgery. The spirometric and gas exchange parameters included residual volume, total lung capacity, inspiratory capacity, forced vital capacity, forced expiratory volume in one second, diffusion capacity for CO, and arterial blood gas. A 6-minute walk distance (6MWD) test was performed. As to preoperative assessment, most spirometric parameters and 6MWD were significantly improved after 3 months and slightly 3 years after LVRS. Gas exchange parameters were significantly improved 3 months after surgery, but returned to the preoperative levels after 3 years. LVRS may significantly improve pulmonary function in patients with severe COPD indicating for LVRS. Mid-term pulmonary function 3 years after surgery can be decreased to the level at 3 months after surgery. Three years after LVRS, lung volume and pulmonary ventilation function can be significantly improved, but the improvement in gas exchange function was not significant.

Dietary vitamin K intakes, chronic obstructive pulmonary disease, adult asthma, and lung function: a prospective cohort study in the UK Biobank.