Untreated Chronic Obstructive Pulmonary Disease Research Articles

Airway Smooth Muscle Cell Mitochondria Damage and Mitophagy in COPD via ERK1/2 MAPK.

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible deterioration of the airway wall. Cigarette smoking is the major trigger, and in vitro studies showed that cigarette smoke extract (CSE) induced mitophagy in airway epithelial cells via oxidative stress, but this mechanism was not studied in airway smooth muscle cells (ASMCs). Primary ASMCs isolated from COPD patients or non-disease donors were investigated for CSE-induced remodeling and mitochondria structure. Proteins were assessed by Western blots for remodeling: collagen type-I, α-smooth muscle actin (α-SMA) and fibronectin; autophagy: beclin-1, protein62 (p62), light chain (LC)3A/B; mitochondria activity: mitochondrially encoded cytochrome c oxidase II & -IV (MTCO2, MTCO4), peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α); lysosomes: early endosome antigen 1, lysosome activated membrane protein 1; and cell signaling: extracellular signal regulated kinase (ERK1/2). Lysotracker and Mitotracker were used to monitor mitochondria morphology and organelle co-localization. Compared with controls, untreated COPD ASMCs showed lower collagen type-I and α-SMA expressions, but increased fibronectin levels. CSE further downregulated collagen type-I and α-SMA expression, but upregulated fibronectin. CSE decreased PGC-1α, MTCO2, and MTCO4, but increased beclin-1, p62, and LC3. CSE upregulated mitophagy and lysosomes activity via ERK1/2 phosphorylation. In vitro, cigarette smoke induced the deterioration of ASMCs, which might explain the tissue loss and structural remodeling in COPD bronchi. The results suggest that preventing exceeded mitophagy in ASMCs might present a novel therapeutic target for COPD.

Efficacy of preoperative inhaled LAMA/LABA combinations in patients with lung cancer and untreated COPD.

Chronic obstructive pulmonary disease (COPD) is associated with a high incidence of postoperative pulmonary complications (PPCs). When untreated COPD is found before lung cancer surgery, we have been actively intervening therapeutically with inhaled long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combinations. We investigated the efficacy of preoperative LAMA/LABA treatment. We reviewed data from 261 patients who underwent pulmonary resection for primary lung cancer. Of these, 59 patients showed unrecognized obstructive ventilatory impairment on respiratory function testing. We administered inhaled drugs for 38 patients, of whom 22 patients treated with LAMA/LABA combinations and diagnosed with COPD were retrospectively analyzed regarding improvement of respiratory function and postoperative course. Median duration of LAMA/LABA treatment was 19.5 days (interquartile range (IQR), 10.5-28.3 days). Percentage predicted vital capacity (%VC) (pretreatment: 95.6%, IQR 91.9-111.7 vs. posttreatment 102.8%, IQR 92.3-113.0), forced expiratory volume in 1 s (FEV1) (1.76 L, 1.43-2.12 vs. 2.00 L, 1.78-2.40), forced VC (FVC) (2.96 L, 2.64-3.47 vs. 3.22 L, 2.95-3.74) and percentage predicted FEV1 (80.1%, 68.4-97.0 vs. 91.6%, 80.3-101.9) were all significantly improved (P<0.05 each). FEV1/FVC tended to be improved, but not significantly. No significant difference in improvement of respiratory function was seen between short-term (≤2 weeks) and normal-term (>2 weeks) treatment. PPCs occurred in 4 of 22 patients (18.2%), showing no significant difference compared to patients with COPD previously treated with inhaled drugs (2/20; 10.0%). Respiratory function is improved by preoperative LAMA/LABA treatment even in the short term. Starting treatment allows even COPD patients diagnosed on preoperative screening to experience the same frequency of PPCs as previously treated patients.

Preoperative management using inhalation therapy for pulmonary complications in lung cancer patients with chronic obstructive pulmonary disease

ObjectiveThis study aimed to investigate whether perioperative inhalations of long-acting beta-agonists (LABAs) or long-acting muscarinic antagonists (LAMAs) might decrease the incidence of postoperative complications in lung cancer patients with chronic obstructive pulmonary disease (COPD).MethodsWe retrospectively analyzed 108 patients with COPD who underwent pulmonary resections for primary lung cancer at our hospital between January 2013 and January 2016 to determine the association between the incidence of postoperative complications (e.g., prolonged air leakage and pneumonia) and the use of LABAs or LAMAs.ResultsThirty patients with COPD experienced postoperative complications (27.8%): Fourteen patients had prolonged air leakages (more than 7 days), ten patients developed pneumonia. The frequency of these postoperative pulmonary complications was significantly higher among the patients with COPD (24/108 cases, 22.2%), compared with the frequency among non-COPD patients (15/224 cases, 6.7%). Inhaled bronchodilators, such as LAMA or LABA, were prescribed for 34 of the 108 patients with COPD; the remaining 74 patients were not treated with bronchodilators. Pulmonary complications were significant lower among the LAMA or LABA users (3/34 cases, 8.8%) than among the untreated COPD patients (21/74 cases, 28.4%).ConclusionFor lung cancer patients with COPD, preoperative management using LABA or LAMA bronchodilators and smoking cessation can reduce the frequency of postoperative pulmonary complications after surgical lung resection. LAMA or LABA inhalation might be useful for not only perioperative care, but also for the long-term survival of COPD patients after surgery.

Metabolomic profiling of doxycycline treatment in chronic obstructive pulmonary disease

Serum metabolic profiling can identify the metabolites responsible for discrimination between doxycycline treated and untreated chronic obstructive pulmonary disease (COPD) and explain the possible effect of doxycycline in improving the disease conditions. 1H nuclear magnetic resonance (NMR)-based metabolomics was used to obtain serum metabolic profiles of 60 add-on doxycycline treated COPD patients and 40 patients receiving standard therapy. The acquired data were analyzed using multivariate principal component analysis (PCA), partial least-squares-discriminant analysis (PLS-DA), and orthogonal projection to latent structure with discriminant analysis (OPLS-DA). A clear metabolic differentiation was apparent between the pre and post doxycycline treated group. The distinguishing metabolites lactate and fatty acids were significantly down-regulated and formate, citrate, imidazole and l-arginine upregulated. Lactate and folate are further validated biochemically. Metabolic changes, such as decreased lactate level, inhibited arginase activity and lowered fatty acid level observed in COPD patients in response to add-on doxycycline treatment, reflect the anti-inflammatory action of the drug. Doxycycline as a possible therapeutic option for COPD seems promising.

Influence of indacaterol on daily physical activity in patients with untreated chronic obstructive pulmonary disease

BackgroundIndacaterol, a once-daily, long-acting β2-agonist, may improve not only respiratory function, dyspnea symptoms, and quality of life, but also physical activity for patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the effect of 12-week indacaterol therapy on daytime physical activity in patients with untreated COPD.MethodsThe subjects were stable and untreated COPD outpatients with a percent predicted forced expiratory volume in 1 second (%FEV1) below 80%. Baseline assessments included clinical assessment, respiratory function testing, arterial blood gas analysis, the COPD assessment test (CAT™), and the Medical Outcomes Study 36-Item Short-Form Health Survey, Japanese version 2 (SF-36v2®). Patients underwent monitoring by uniaxial accelerometer before and after 12 weeks once-daily inhalation of indacaterol 150 μg/day.ResultsEighteen patients were evaluable. Patient characteristics included a mean age of 74.2 years, and three patients were current smokers. Indacaterol improved mean (± standard deviation [SD]) %FEV1 from 55.2% (±17.9%) to 61.0% (±17.3%) (P=0.003), CAT scores from 16.4 (±10.2) points to 12.4 (±8.2) points (P=0.04), some scales of the SF-36v2 (physical component summary, 41.6±9.7 points to 45.1±7.9 points, P=0.03), and number of daily steps (3,311.5±2,103.3 steps/day to 3,841.8±2,096.8 steps/day, P=0.02), but did not affect daily energy expenditure (85.0±77.2 kcal change to 90.9±56.8 kcal, P=0.29) or exercise duration of an intensity of level 1 or more (36.4±23.9 minutes increase to 40.8±21.6 minutes, P=0.12).ConclusionTwelve weeks of indacaterol improved respiratory function and quality of life, but did not significantly affect physical activity in patients with moderate-to-severe COPD.

A comparison of health, health behavior, and access between farm and nonfarm populations in rural New York state.

Recent technological and demographic changes in US agriculture raise questions about whether the previously observed benefits of the agricultural lifestyle persist. In 2009, researchers conducted a household survey of 9,612 adults (aged 20+) in a rural region of Upstate New York. Data on health status, health behaviors, and health care access among farmers and rural nonfarm residents were compared. After adjustment for age, gender, education, and having a regular health care provider, male farmers had elevated prevalence of asthma (OR: 1.82, 95% CI: 1.05-3.16) and untreated chronic obstructive pulmonary disease (COPD) (OR: 3.17, 95% CI: 1.12-9.01). Farmers had significantly lower hypercholesterolemia (OR: 0.70, 95% CI: 0.50-0.99), but not lower prevalence of heart disease or stroke. Farmers had lower rates of smoking (OR: 0.60, 95% CI: 0.40-0.89) and higher rates of hard physical labor (OR: 2.61, 95% CI: 1.83-3.72) than nonfarmers, but they had notably worse health behavior prevalence relative to various types of screening, vaccinations, and having a regular medical care provider (OR: 0.53, 95% CI: 0.39-0.71). The farm population is becoming more like the rural nonfarm population with regard to health outcomes and lifestyle, yet it remains notably poorer with regard to prevention. Targeted outreach is needed to increase prevention within the agricultural community.

RETRACTED ARTICLE: Inhaled tiotropium to prevent postoperative cardiopulmonary complications in patients with newly diagnosed chronic obstructive pulmonary disease requiring lung cancer surgery

A new diagnosis of chronic obstructive pulmonary disease is often made during the evaluation of patients requiring lung cancer surgery. The objective of the present study was to evaluate the clinical effects of inhaled tiotropium on the postoperative cardiopulmonary complications in patients with untreated chronic obstructive pulmonary disease requiring lung cancer surgery. A retrospective study involving 104 consecutive patients with moderate to severe chronic obstructive pulmonary disease who underwent a lobectomy for lung cancer at two specialized thoracic centers between April 2008 and October 2011 was performed. The results were compared between patients who did and did not receive inhaled tiotropium during the perioperative period. The primary endpoint was the incidence of postoperative cardiopulmonary complications. The postoperative white blood cell counts and C-reactive protein levels as biomarkers of inflammation were also examined. The incidence of postoperative cardiopulmonary complications was significantly lower in the tiotropium group than in the control group (18 vs. 48 %, P = 0.001). Patients in the tiotropium group also showed significantly lower white blood cell counts and C-reactive protein levels postoperatively. Inhaled tiotropium treatment during the perioperative period had a prophylactic effect on postoperative cardiopulmonary complications in patients with newly diagnosed chronic obstructive pulmonary disease requiring lung cancer surgery.

Evaluation of Right Ventricular Remodeling Using Cardiac Magnetic Resonance Imaging in Co-Existent Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea

Untreated chronic obstructive pulmonary disease (COPD) co-existing with obstructive sleep apnea (OSA), also known as overlap syndrome, has higher cardiovascular mortality than COPD alone but its underlying mechanism remains unclear. We hypothesize that the presence of overlap syndrome is associated with more extensive right ventricular (RV) remodeling compared to patients with COPD alone. Adult COPD patients (GOLD stage 2 or higher) with at least 10 pack-years of smoking history were included. Overnight laboratory-based polysomnography was performed to test for OSA. Subjects with an apnea-hypopnea index (AHI) >10/h were classified as having overlap syndrome (n = 7), else classified as having COPD-only (n = 11). A cardiac MRI was performed to assess right and left cardiac chambers sizes, ventricular masses, and cine function. RV mass index (RVMI) was markedly higher in the overlap group than the COPD-only group (19 ± 6 versus 11 ± 6; p = 0.02). Overlap syndrome subjects had a reduced RV remodeling index (defined as the ratio between RVMI and RV end-diastolic volume index) compared to the COPD-only group (0.27 ± 0.06 versus 0.18 ± 0.08; p = 0.02). In the overlap syndrome subjects, the extent of RV remodeling was associated with severity of oxygen desaturation (R2 = 0.65, p = 0.03). Our pilot results suggest that untreated overlap syndrome may cause more extensive RV remodeling than COPD alone.

Retracted: Low-dose human atrial natriuretic peptide for the prevention of postoperative cardiopulmonary complications in chronic obstructive pulmonary disease patients undergoing lung cancer surgery

Lung cancer patients with chronic obstructive pulmonary disease are at an increased risk of respiratory and cardiovascular complications after pulmonary resection. The objective of the present study was to evaluate the clinical effects of low-dose human atrial natriuretic peptide (hANP) on postoperative cardiopulmonary complications in untreated chronic obstructive pulmonary disease patients undergoing lung cancer surgery. Of 824 patients who underwent an elective pulmonary resection procedure for lung cancer in two specialized thoracic centres between 2008 and 2011, 202 consecutive patients who had airflow limitation before surgery were included in this retrospective study. The results were compared between patients who did and those who did not receive hANP during the perioperative period. The primary endpoint was the incidence of postoperative cardiopulmonary complications. Postoperative haemodynamics, white blood cell (WBC) counts and C-reactive protein (CRP) levels were also examined. Furthermore, propensity score matching analysis was used to reduce treatment selection bias from patient characteristics. The incidence of postoperative cardiopulmonary complications was significantly lower in the hANP group than in the control group (14 vs 36%, P < 0.01). The propensity score matching analysis confirmed the significantly decreased frequency of postoperative cardiopulmonary complications in the hANP group. Patients in the hANP group showed significantly lower WBC counts and serum CRP levels postoperatively. Treatment with hANP during the perioperative period had a prophylactic effect against postoperative cardiopulmonary complications in chronic obstructive pulmonary disease patients undergoing lung cancer surgery.

Carotid atherosclerosis in patients with untreated chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation. To evaluate carotid artery intima-media thickness (IMT), high sensitivity C-reactive protein (hsCRP) and their correlation in newly diagnosed untreated patients with COPD. Post-bronchodilator spirometry, carotid artery IMT and blood tests were measured in patients with COPD (COPD group). Age, sex, body mass index, smoking status and smoking amount were compared with matched healthy subjects (non-COPD group). Participants taking medications and/or with a history of hypertension, diabetes mellitus, dyslipidaemia, COPD or cardiovascular disease were excluded. A total of 126 patients (COPD group 42, non-COPD group 84) were enrolled. The IMT and hsCRP of the COPD group were significantly higher than in the non-COPD group (P < 0.05). The decrease in the forced expiratory volume in 1 second/forced vital capacity (FEV(1)/FVC) ratio and FEV(1) was significantly correlated with an increase in the hsCRP and IMT (P < 0.05); there was no correlation between the IMT and hsCRP (P = 0.152). In newly diagnosed untreated patients with COPD, the carotid artery IMT and hsCRP were significantly higher than in healthy subjects. These findings suggest that systemic inflammation may play a potential role in preclinical atherosclerosis in COPD.

Bone loss in patients with untreated chronic obstructive pulmonary disease is mediated by an increase in bone resorption associated with hypercapnia.

This study sought to determine whether the bone loss in untreated chronic obstructive pulmonary disease (COPD) is associated with hypercapnia and/or respiratory acidosis. Bone mineral density (BMD) measured at the distal forearm of the nondominant arm (with peripheral quantitative computed tomography [pQCT]) and serum markers of bone turnover were determined in 71 male patients with untreated COPD and 40 healthy male subjects who matched the patients in age, weight, and body mass index (BMI). The COPD patients, compared with controls, had reduced pulmonary functions, lower arterial pH, and elevated arterial partial pressure of CO2 (PCO2) The BMD (in T score) was significantly lower in COPD patients than that in control subjects (-1.628 +/- 0.168 vs. -0.058 +/- 0.157; p < 0.001). The BMD of COPD patients correlated positively with arterial pH (r = 0.582; p < 0.001), negatively with PCO2 (r = -0.442; p < 0.001), and negatively with serum cross-linked telopeptide of type I collagen (ICTP), a bone resorption marker (r = -0.444; p < 0.001) but not with serum osteocalcin, a bone formation marker. Serum ICTP, but not osteocalcin, correlated with PCO2 (r = 0.593; p < 0.001) and arterial pH (r = -0.415; p < 0.001). To assess the role of hypercapnia, COPD patients were divided into the hypercapnic (PCO2 > 45 mm Hg; n = 35) and eucapnic (PCO2 = 35-45 mm Hg) group (n = 36). Patients with hypercapnia had lower BMD, lower arterial pH, and higher serum ICTP than did patients with eucapnia. Arterial pH and serum ICTP of eucapnic patients were not different from those of controls. To evaluate the role of uncompensated respiratory acidosis, COPD patients with hypercapnia were subdivided into those with compensatory respiratory acidosis (pH > or = 7.35; n = 20) and those with uncompensated respiratory acidosis (pH < 7.35; n = 15). The BMD and serum ICTP were not different among the two subgroups. In conclusion, this study presents the first associative evidence that the bone loss in COPD is at least in part attributed to an increased bone resorption that is associated primarily with hypercapnia rather than uncompensated respiratory acidosis.

Decreased bone formation, mineralization, and enhanced resorption in calcium-deficient rats

Decreased bone formation, mineralization, and enhanced resorption in calcium-deficient rats