Gender difference in plasma fatty-acid-binding protein 4 levels in patients with chronic obstructive pulmonary disease

COPD (chronic obstructive pulmonary disease) is characterized by airway inflammation and increases the likelihood of the development of atherosclerosis. Recent studies have indicated that FABP4 (fatty-acid-binding protein 4), an intracellular lipid chaperone of low molecular mass, plays an important role in the regulation of inflammation and atherosclerosis. We carried out a preliminary clinical study aiming at investigating the relationships between circulating FABP4 levels in patients with COPD and inflammation and lung function. We enrolled 50 COPD patients and 39 healthy controls in the study. Lung function tests were performed in all subjects. Plasma levels of FABP4 and adiponectin, TNFα (tumour necrosis factor α) and CRP (C-reactive protein) were measured. The correlations between FABP4 and lung function, adipokine (adiponectin), inflammatory factors and BMI (body mass index) were analysed. Compared with both males with COPD and healthy females, plasma FABP4 levels in females with COPD were significantly increased. Adiponectin and CRP levels were significantly higher in patients with COPD. Furthermore, we found that FABP4 levels were inversely correlated with FEV₁% predicted (FEV₁ is forced expiratory volume in 1 s) and positively correlated with adiponectin and TNFα in COPD patients. In addition, a positive correlation between plasma FABP4 and CRP was found in females with COPD. However, FABP4 levels were not correlated with BMI. Our results underline a gender difference in FABP4 secretion in stable COPD patients. Further studies are warranted to clarify the exact role of FABP4 in the pathogenesis of COPD.     

Human serum antibody response against iron-repressible outer membrane proteins of Helicobacter pylori

Abstract In Helicobacter pylori , in vitro iron limitation induces the expression of several iron repressible outer membrane proteins (IROMPs), which are not expressed under normal growth conditions. To substantiate their proposed role in virulence of H. pylori , we determined whether these IROMPs are also expressed in vivo. Therefore, we tested whether sera of patients with H. pylori infection contained antibodies against IROMPs. All sera from 20 H. pylori positive patients showed a clear immune response against a 77 kDa heme-binding IROMP in an immunoblot assay. Antibody responses against the other IROMPs were also found, but with lower frequencies. Serum samples from 18 patients negative for H. pylori infection did not show any immunoreactivity with IROMPs. These results indicate that the IROMPs of H. pylori are immunogenic and are expressed in vivo.     

Genotypes of the vitamin D-binding protein gene in patients with chronic obstructive pulmonary disease and in the healthy population of the Republic Bashkortostan

Allele and genotype frequency distributions of the vitamin D-binding protein gene (DBP) were studied in patients with chronic obstructive pulmonary disease (COPD, N = 298) and healthy individuals (N = 237) from two ethnic groups (Tatars and Russians) resident in the Republic Bashkortostan. The DBP genotype frequency distribution significantly differed between Tatars and Russians (X ² = 8.854, df = 5, P = 0.04). The DBP allele frequency distribution was similar in healthy subjects of both ethnic groups, with allele frequency decreasing as GC*1S > GC*1F > GC*2. The most common DBP genotype was GC*1F/1S in Tatars (36.79%) and GC*1S/2 in Russians (34.62%). It was demonstrated that, in Tatars, the genotype GC*1F/1S is protective against COPD, its frequency being significantly lower in COPD patients than in healthy subjects (19.85% vs. 36.79%; X ² = 7.622, P = 0.0067, P _cor = 0.0335; OR = 0.42, 95%CI 0.42–0.95). On the other hand, the genotype GC*1F/2 was more common among COPD patients than among healthy individuals (19.08% vs. 8.49%; X ² = 4.52, P = 0.033, P _cor = 0.165; OR = 2.54, 95%CI 1.067–6.20). No differences in DBP genotype and allele frequency distributions was found between COPD patients and healthy individuals in the Russian population.     

Contribution of cuproptosis and Cu metabolism-associated genes to chronic obstructive pulmonary disease

Airway epithelial cell injury plays a crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, a novel form of Cu-induced programmed cell death known as cuproptosis has not yet been thoroughly investigated in the context of COPD. Clinical reports have suggested that high copper exposure may increase the risk of COPD. In this study, we aimed to determine the expression and potential functions of cuproptosis-related genes and genes associated with copper metabolism in COPD. We initially identified 52 copper metabolism-related genes based on a review of the literature. Subsequently, we calculated the expression levels of these genes using data from four GEO datasets. To gain insights into the activated signalling pathways and underlying mechanisms in COPD patients, we conducted Gene Ontology (GO) and KEGG pathway analyses, examined protein–protein interactions, and performed weighted correlation network analysis. Our findings revealed that 18 key copper metabolism-related genes, including 5 cuproptosis-related genes, were significantly enriched in signalling pathways and biological processes associated with the development of COPD. Further analysis of clinical data and animal experiments confirmed the high expression of certain cuproptosis key regulators, such as DLD and CDKN2A, in both healthy smokers and COPD smokers. Additionally, these regulators exhibited abnormal expression in a COPD rat model. Notably, copper content was found to be elevated in the lung tissues of COPD rats, suggesting its potential involvement in cuproptosis. These findings provide an experimental foundation for further research into the role of cuproptosis in COPD. Targeting copper metabolism-related genes may represent an effective approach for the treatment of COPD.     

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

Background

The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Methods

In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV₁)/forced vital capacity ratio of ≤70% and FEV₁ <80% of the predicted value. The primary endpoint was trough FEV₁ at 12 and 28 weeks. Secondary endpoints were health status measured by St George''s Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.

Results

At 12 and 28 weeks, aclidinium improved trough FEV₁ versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies.

Conclusion

Aclidinium is effective and well tolerated in patients with moderate to severe COPD.

Trial registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00363896","term_id":"NCT00363896"}}NCT00363896 (ACCLAIM/COPD I) and {"type":"clinical-trial","attrs":{"text":"NCT00358436","term_id":"NCT00358436"}}NCT00358436 (ACCLAIM/COPD II).     

Circadian rest-activity rhythm in chronic obstructive pulmonary disease

To characterize circadian rest-activity rhythm in COPD, 26 cases (66.9 ± 8.5y) and 15 controls (63.0 ± 10.7y) were assessed by actimetry. Rhythm fragmentation was measured by intradaily variability (IV), while synchronization to the 24-h light-dark cycle was measured by interdaily stability (IS). The average activity during the least active 5-h period (L5) and the average activity during the most active 10-h period (M10) were used to calculate the relative amplitude mean [RAm = (M10-L5)/(M10+L5)]. COPD patients presented higher IVm (0.242 ± 0.097 vs 0.182 ± 0.063) and L5 (36.849 ± 18.239 vs 19.888 ± 12.268) and lower RAm (0.696 ± 0.134 vs 0.833 ± 0.093) than controls. Future studies on the effects of chronotherapy measures in COPD are warranted.     

慢性阻塞性肺疾病大鼠海马区和血清中脑源性神经营养因子蛋白的表达变化

本文旨在探讨脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)在慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)大鼠模型海马区和血清中的表达情况,以及了解吸烟和气管内注入脂多糖的干预是否参与BDNF表达变化.采用被动...     

Low bone mineral density in men with chronic obstructive pulmonary disease

Background

Osteoporosis is common in patients with COPD but the likely multi-factorial causes contributing to this condition (e.g. sex, age, smoking, therapy) mask the potential contribution from elements related to COPD. In order to study osteoporosis and bone mineral density (BMD) related to COPD, we studied a well-defined group of patients and controls.

Methods

BMD, forced expiratory volume in one second (FEV₁), circulating bone biomarkers and biochemistry were determined in 30 clinically stable male ex-smokers with confirmed COPD and 15 age matched "ex-smoker" male controls. None of the patients were on inhaled corticosteroids or received more than one short course of steroids.

Results

Mean (SD) FEV₁% predicted of patients was 64(6)%, the majority having Global Initiative for Chronic Obstructive Lung Disease (GOLD) II airflow obstruction. There were 5/30 patients and 1/15 controls who were osteoporotic, while a further 17 patients and 5 controls were osteopenic. The BMD at the hip was lower in patients than controls, but not at the lumbar spine. Mean values of procollagen type 1 amino-terminal propeptide and osteocalcin, both markers of bone formation, and Type 1 collagen β C-telopeptide, a marker of bone resorption, were similar between patients and controls. However, all bone biomarkers were inversely related to hip BMD in patients (r = -0.51, r = -0.67, r = -0.57, p < 0.05) but did not relate to lumbar spine BMD. 25-OH Vitamin D was lower in patients.

Conclusions

Men with COPD had a greater prevalence of osteoporosis and osteopenia than age matched male controls, with a marked difference in BMD at the hip. Bone biomarkers suggest increased bone turnover.     

Glutathione cycle in stable chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidant/antioxidant imbalance. Glutathione is the most abundant cellular low‐molecular weight thiol and the glutathione redox cycle is the fundamental component of the cellular antioxidant defence system. Concentration of total glutathione and catalytic activities of glutathione peroxidase and glutathione reductase were determined in peripheral blood of patients (n = 109) and healthy subjects (n = 51). Concentration of total glutathione in patients was not changed in comparison to healthy controls. However, we found statistically significant difference between patients with moderate and severe disease stages. Glutathione reductase activity was increased, while glutathione proxidase activity was decreased in the patients with COPD, when compared to healthy controls. We found no significant difference in glutathione peroxidase and glutathione reductase activities between stages. Patients who smoked had lower concentration of total glutathione compared with former smokers and never‐smoking patients. Lung function parameters were inversely associated with glutathione level. Evidence is presented for differential modulation of glutathione peroxidase and glutathione reductase activities in peripheral blood of patients with stable COPD. We suppose that in addition to glutathione biosynthesis, glutathione reductase‐dependent regulation of the glutathione redox state is vital for protection against oxidative stress. Copyright © 2010 John Wiley & Sons, Ltd.     

Systemic inflammatory profile and response to anti-tumor necrosis factor therapy in chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease (COPD) is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers. Despite correlative evidence for a role for tumor necrosis factor-alpha in the pathogenesis of COPD, the anti-tumor necrosis factor-alpha, infliximab did not show clinical efficacy in a double-blind, placebo-controlled, phase II clinical trial. This study sought to evaluate the systemic inflammatory profile associated with COPD and to assess the impact of tumor necrosis factor neutralization on systemic inflammation.

Methods

Serum samples (n = 234) from the phase II trial were collected at baseline and after 24 weeks of placebo or infliximab. Additionally, baseline serum samples were obtained from an independent COPD cohort (n = 160) and 2 healthy control cohorts (n = 50; n = 109). Serum concentrations of a broad panel of inflammation-associated analytes were measured using a 92-analyte multiplex assay.

Results

Twenty-five proteins were significantly elevated and 2 were decreased in COPD, including highly elevated CD40 ligand, brain-derived neurotrophic factor, epidermal growth factor, acute-phase proteins, and neutrophil-associated proteins. This profile was largely independent of smoking status, age, and clinical phenotype. The majority of these associations of serum analytes with COPD are novel findings. Increased serum creatine kinase-muscle/brain and myoglobin correlated modestly with decreased forced expiratory volume at 1 second, suggesting cardiac involvement. Infliximab did not affect this systemic inflammatory profile.

Conclusions

A robust systemic inflammatory profile was associated with COPD. This profile was generally independent of disease severity. Because anti-tumor necrosis factor-alpha did not influence systemic inflammation, how to control the underlying pathology beyond symptom suppression remains unclear.

Trial Registration

ClinicalTrials.gov, No.: NCT00056264.     

Infectious exacerbations of chronic obstructive pulmonary disease associated with respiratory viruses and non-typeable Haemophilus influenzae

Infectious exacerbations of chronic obstructive pulmonary disease (COPD) have been reported to occur with both viral and bacterial pathogens. In this study, 35 exacerbations associated with the isolation of non-typeable Haemophilus influenzae from sputum were identified as part of a prospective longitudinal study. Samples from these patients were subjected to immunoassays to identify a new immune response to the homologous isolate of non-typeable H. influenzae to more accurately assess a bacterial etiology. These patients also were studied carefully for evidence of viral infection using viral culture, serology and polymerase chain reaction-based assays. Sixteen of 35 exacerbations (45.7%) were associated with evidence of acute viral infection and 11 of the 35 exacerbations (31.4%) were associated with the development of new serum IgG to homologous non-typeable H. influenzae. Overall, evidence of infection with a respiratory virus or non-typeable H. influenzae was seen in 24 of 35 exacerbations (68.6%). No association between viral infection and immune response to non-typeable H. influenzae was observed, although a trend toward an immune response to non-typeable H. influenzae and absence of viral infection was seen. The results show that exacerbations in adults with COPD were associated with infection caused by virus alone, non-typeable H. influenzae alone, or virus and non-typeable H. influenzae simultaneously.     

地塞米松联合缬沙坦对慢性阻塞性肺疾病小鼠保护作用及机制探讨*

目的: 评估地塞米松联合缬沙坦对香烟所致慢性阻塞性肺疾病(COPD)小鼠的保护作用。方法: 40只C57BL/6小鼠随机分为(n=8):对照组、COPD组、地塞米松组、缬沙坦组和地塞米松+缬沙坦联合处理组。COPD组小鼠持续8周进行香烟暴露;在香烟暴露基础上,地塞米松组小鼠在5~8周香烟暴露前腹腔注射地塞米松(2 mg/kg);缬沙坦组小鼠在1~8周香烟暴露前腹腔注射缬沙坦(30 mg/kg);地塞米松+缬沙坦联合处理组小鼠腹腔注射地塞米松(2 mg/kg)和缬沙坦(30 mg/kg)。8周后收集各组小鼠肺组织及支气管肺泡灌洗液(BALF),评估肺组织病理学评分及BALF中超氧化物歧化酶(SOD)和基质金属蛋白酶9(MMP-9)活性,以及丙二醛(MDA)、细胞内黏附分子1(ICAM-1)、C反应蛋白(CRP)和一氧化氮(NO)含量。结果: 与对照组相比,COPD组小鼠存在肺气肿和肺泡充血,BALF中MDA、ICAM-1、MMP-9、CRP和淋巴细胞升高,SOD、巨噬细胞和NO降低(P均＜0.05)。与COPD组相比,地塞米松或缬沙坦组小鼠肺气肿和肺泡充血无明显改善,BALF中SOD 和NO升高,MDA、淋巴细胞和巨噬细胞降低(P均＜0.05)。与地塞米松或缬沙坦组相比较,地塞米松+缬沙坦联合处理组能更有效预防香烟引起的肺气肿和肺泡充血,降低BALF中MDA、ICAM-1、MMP-9、CRP和淋巴细胞,升高SOD、巨噬细胞和NO(P均＜ 0.05)。结论: 地塞米松联合缬沙坦通过抑制氧化应激和炎症,可以更有效在COPD小鼠中发挥保护作用。     

肺部微生物组通过炎症反应介导慢性阻塞性肺疾病转化为肺癌的研究进展

肺部微生物组存在于呼吸道和实质组织中,通过菌群紊乱、代谢产物、炎症反应、免疫反应、基因毒性等方面介导肺部损伤。随着肺部微生物组的深入研究,发现肺部微生物组的相关活动与慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)和肺癌息息相关,能够促使COPD向肺癌的转变。本文主要介绍了肺部微生物组稳态及其通过炎症反应导致COPD和肺癌,重点探讨了肺部微生物组如何通过炎症反应介导COPD转化为肺癌,以期为COPD和肺癌的临床预防、优化治疗以及新型药物设计提供新的理论依据。     

Association of polymorphisms of the CYP1A1 and CYP1A2 cytochrome P450 genes with chronic obstructive pulmonary disease in Bashkortostan

The frequencies of polymorphisms of CYP1A1 (2455A/G, 3801T/C) and CYP1A2 (?2464T/delT, ?163C/A) were determined in healthy residents of Bashkortostan (Russians, Tatars, and Bashkirs) and tested for association with chronic obstructive pulmonary disease (COPD). Interethnic differences in the frequency distribution of the CYP1A1 and CYP1A2 polymorphisms were significant. In Tatars and Russians, the CYP1A1 and CYP1A2 haplotype frequencies were similar (χ² = 0.973, df = 3, P = 1.00 and χ² = 1.546, df = 3, P = 0.92, respectively). In Bashkirs, the CYP1A1 haplotype frequencies significantly differed from those in Russians and Tatars (χ² = 12.328, df = 3, P = 0.008 and χ² = 9.218, df = 3, P = 0.034, respectively) owing to a high frequency of CYP1A1*2B (10.17%). Similarly, Bashkirs differed from Russians and Tatars in the CYP1A2 haplotype frequencies (χ² = 18.779, df = 3, P = 0.0001 and χ² = 14.326, df = 3, P = 0.003, respectively). The frequency of the CYP1A2*1D haplotype in Bashkirs was 11.02% in contrast to 2.36% in Tatars and 1.61% in Russians. Allele *D of the CYP1A2 ?2467delT polymorphism was associated with COPD in Tatars (OR = 1.83, 95%CI 1.24–2.71, χ² = 9.48, P = 0.003). CYP1A2*1D was associated with an increased risk of COPD (8.65% vs. 2.36% in controls, χ² = 9.733, P = 0.0027, P _cor = 0.008, OR = 3.908, 95%CI 1.56–10.19). Haplotype CYP1A2*1A was significantly less frequent in patients with COPD (21.05% vs. 30.74%, χ² = 6.319, P = 0.0127, P _cor = 0.038, OR = 0.6012, 95%CI 0.402–0.898). The CYP1A1 polymorphisms were not associated with COPD in residents of Bashkortostan.     

Diagnosis of ovine enzootic abortion using an indirect ELISA (rOMP91B iELISA) based on a recombinant protein fragment of the polymorphic outer membrane protein POMP91B of Chlamydophila abortus

Chlamydophila abortus is of major economic importance worldwide as one of the principal causes of abortion in sheep. Serological diagnosis of infection by the complement fixation test (CFT) is complicated by false positive reactions resulting from cross-reactive antibodies to Chlamydophila pecorum. To improve diagnosis an indirect enzyme-linked immunosorbent assay (iELISA) based on a recombinant protein fragment of the C. abortus polymorphic outer membrane protein POMP91B (rOMP91B iELISA) was assessed using a panel of 281 sera from experimentally and naturally infected sheep. The iELISA performed well, being more sensitive (84.2%) and specific (98.5%) than the CFT. Furthermore, the iELISA was better at differentiating C. abortus- from C. pecorum-infected animals. The new rOMP91B iELISA test will prove a valuable tool for the routine serodiagnosis of C. abortus infection.     

Evaluation of real-time PCR for the detection and quantification of bacteria in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) embraces a number of pathological processes including chronic bronchitis, chronic bronchiolitis and emphysema. The chronic and progressive course of COPD is often aggravated by short periods of increasing symptoms. Respiratory tract infections (RTIs) are the most common causes of COPD exacerbations. Detection and enumeration of respiratory bacteria are important techniques in diagnosing RTIs and in the validation of new treatment methods. We describe here the development and evaluation of real-time PCR assays for the simultaneous direct detection and quantification of a range of respiratory bacteria in individuals with COPD during stable periods and during acute exacerbations of the disease. Sputum samples from 30 subjects in a COPD study were analysed, and results compared with the current gold standard of culture. Real-time PCR assays proved highly sensitive, with no cross-reactivity with other species. The prevalence of bacteria detected by real-time PCR compared with that by culture was substantially higher for Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus spp. and Moraxella catarrhalis. Multiple pathogens were also found with real-time PCR but were not detected by culture. This study demonstrates the potential of such methods in the detection and enumeration of respiratory bacteria.     

Dietary modulation of oxidative stress in chronic obstructive pulmonary disease patients

Abstract

A total of 267 clinically stable chronic obstructive pulmonary disease (COPD) patients provided complete data about diet and oxidative stress markers in order to assess the relationship between antioxidant rich food groups and nutrients, and serum markers of oxidative stress in COPD. Dietary data of the last 2 years was assessed using a validated food frequency questionnaire (122 items). Levels of carbonyls, nitrotyrosine, malondialdehyde and reduced glutathione (GSH) were measured in serum. Vitamin E intake was inversely associated with levels of carbonyls (p = 0.05) and olive oil was positively associated with GSH levels (p = 0.01), in active smokers. Intake of vegetables was related to a decrease of malondialdehyde levels (p = 0.04) in former smokers. No statistically significant associations were found between remaining dietary antioxidants and serum oxidative stress markers. These results provide new data for a potential dietary modulation of systemic oxidative stress in COPD patients, particularly in those that continue smoking.     

Differential coexpression networks in bronchiolitis and emphysema phenotypes reveal heterogeneous mechanisms of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with multiple molecular mechanisms. To investigate and contrast the molecular processes differing between bronchiolitis and emphysema phenotypes of COPD, we downloaded the GSE69818 microarray data set from the Gene Expression Omnibus (GEO), which based on lung tissues from 38 patients with emphysema and 32 patients with bronchiolitis. Then, weighted gene coexpression network analysis (WGCNA) and differential coexpression (DiffCoEx) analysis were performed, followed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis (KEGG) analysis. Modules and hub genes for bronchiolitis and emphysema were identified, and we found that genes in modules linked to neutrophil degranulation, Rho protein signal transduction and B cell receptor signalling were coexpressed in emphysema. DiffCoEx analysis showed that four hub genes (IFT88, CCDC103, MMP10 and Bik) were consistently expressed in emphysema patients; these hub genes were enriched, respectively, for functions of cilium assembly and movement, proteolysis and apoptotic mitochondrial changes. In our re‐analysis of GSE69818, gene expression networks in relation to emphysema deepen insights into the molecular mechanism of COPD and also identify some promising therapeutic targets.