Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients

Background

Acute exacerbations of COPD (AECOPD) are common and strongly influence disease severity and relative healthcare costs. Vitamin D deficiency is frequent among COPD patients and its contributory role in disease exacerbations is widely debated. Our aim was to assess the relationship of serum vitamin D levels with COPD severity and AECOPD.

Methods

Serum vitamin D (25-hydroxyvitamin D) levels were measured in 97 COPD patients and related to lung function, comorbidities, FEV1 decline, AECOPD and hospital admission during the previous year.

Results

Most patients (96%) had vitamin D deficiency, which was severe in 35 (36%). No significant relationship was found between vitamin D and FEV1 or annual FEV1 decline. No difference between patients with and without severe vitamin D deficiency was found in age, gender, BMI, smoking history, lung function, and comorbidities, apart from osteoporosis (60.9% in severe deficiency vs 22.7%, p = 0.001). In multiple logistic regression models, severe deficiency was independently associated with AECOPD [adjusted odds ratios (aOR) of 30.5 (95% CI 5.55, 168), p < 0.001] and hospitalization [aOR 3.83 (95% CI 1.29, 11.4), p = 0.02]. The odds ratio of being a frequent exacerbator if having severe vitamin D deficiency was 18.1 (95% CI 4.98, 65.8) (p < 0.001), while that of hospitalization was 4.57 (95% CI 1.83, 11.4) (p = 0.001).

Conclusions

In COPD patients severe vitamin D deficiency was related to more frequent disease exacerbations and hospitalization during the year previous to the measurement of vitamin D. This association was independent of patients’ characteristics and comorbidities.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0131-0) contains supplementary material, which is available to authorized users.     

自噬与肺部疾病研究进展

自噬(autophagy)是广泛存在于真核细胞中的基本生命现象,是细胞适应环境变化、防御病原微生物侵袭、维持内环境稳定的重要机制．多种肺部疾病中存在自噬活性的变化,自噬与肺部疾病的发生、发展密切相关．自噬在慢性阻塞性肺病、肺气肿、肺癌、肺结核等许多肺部疾病中发生,且发挥重要作用．现从自噬与多种肺部疾病的关系角度进行综述,有助于了解自噬在肺部疾病中发挥的作用,以便进一步研究自噬的调节,为肺部疾病的治疗提供新思路．     

IL-4抑制COPD大鼠肺组织COX-2和PDGF的表达

目的探讨白细胞介素-4(IL-4)对慢性阻塞性肺疾病(COPD)大鼠模型建立的影响,以及COPD肺组织中环氧合酶-2(COX-2)和血小板源性生长因子(PDGF)的表达及IL-4对其表达的影响机制。方法用雄性Wistar大鼠建立吸烟大鼠COPD模型。随机分为对照组,模型组,IL-4组和地塞米松组。用免疫组化法和逆转录聚合酶联反应法(RT-PCR),检测肺组织中COX-2和PDGF-A及PDGF-B的表达情况。结果模型组COX-2和PDGF-A、-B表达明显增高;IL-4组和地塞米松组显著降低。结论IL-4和地塞米松可干预COPD模型的建立;COPD肺组织中COX-2和PDGF的表达显著增高,IL-4和地塞米松可明显降低其表达。     

Detection of polymorphisms at exons 3 (Tyr113-->His) and 4 (His139-->Arg) of the microsomal epoxide hydrolase gene using fluorescence PCR method combined with melting curves analysis

An association between exon 3 polymorphisms of the gene encoding microsomal epoxide hydrolase (mEH) and susceptibility to the development of chronic obstructive pulmonary disease (COPD) has been described. We have developed two methods for detecting polymorphisms at exons 3 (Tyr113-->His) and 4 (His139-->Arg) of the mEH gene based on different melting temperatures (T(m)) of fluorescent-labeled oligonucleotide hybridization probes using single-step assays that combine fluorescence PCR and melting curve analysis (LightCycler methodology). DNA was extracted from blood in 79 COPD patients and 146 healthy controls. Results were compared with those obtained by restriction fragment length polymorphism (RFLP) analysis to detect Tyr113His variants and a single-strand conformation polymorphism (SSCP) assay for His139Arg detection. The T(m) of the exon 3 polymorphisms were 61.3 degrees C for Tyr113 (wild type) and 67.5 degrees C for His113 (mutant). The T(m) values of the exon 4 polymorphisms were 67.5 degrees C for His139 (wild type) and 59.2 degrees C for Arg139 (mutant). The within- and between-run melting peaks for the same allele differed by less than 0.5 degrees C for both the exon 3 and the exon 4 polymorphisms. Thus, melting analysis allowed easy and unambiguous assignment of genotyping by means of the respective melting curves. The proportion of individuals who were homozygous mutant for exon 3 was significantly higher in the COPD group than in the control group (p=0.004). LightCycler fluorescence genotyping of exon 4 polymorphisms correlated perfectly with SSCP results. RFLP assay classified 2 patients as homozygous mutant while LightCycler analysis genotyped them as heterozygous. DNA analysis by PCR and sequencing confirmed the LightCycler result. These high-speed (about 40 min for 32 samples), highly sensitive, and specific small-volume assays with low labor requirements hold great promise as tools for rapid detection of COPD susceptibility.     

益肺胶囊联合乌美溴铵维兰特罗吸入粉雾剂对COPD稳定期患者肺功能、细胞免疫功能和血清bFGF、SIRT1的影响

摘要 目的：探讨益肺胶囊联合乌美溴铵维兰特罗吸入粉雾剂对慢性阻塞性肺疾病（COPD）疾病稳定期患者肺功能、细胞免疫功能和血清碱性成纤维细胞生长因子（bFGF）、沉默信息调节因子1（SIRT1）的影响。方法：纳入我院2021年3月~2022年6月期间收治的COPD稳定期患者104例,按照随机数字表法分为对照组（乌美溴铵维兰特罗吸入粉雾剂治疗,n=52）和观察组（益肺胶囊联合乌美溴铵维兰特罗吸入粉雾剂治疗,n=52）。对比两组临床症状恢复时间、6 min步行试验（6MWT）和COPD评估测试（CAT）评分、肺功能[第1秒用力呼气容积（FEV1）、用力肺活量（FVC）、每分钟最大通气量（MVV）]、细胞免疫功能和血清bFGF、SIRT1水平,观察两组不良反应发生情况。结果：与对照组相比,观察组的肺啰音、咳嗽、咯痰消失时间缩短（P<0.05）。与对照组相比,观察组治疗14 d后6MWT更远,CAT评分更低（P<0.05）。与对照组相比,观察组治疗14 d后FVC、FEV₁、MVV更高（P<0.05）。与对照组相比,观察组治疗14 d后CD3⁺、CD4⁺、CD4⁺/CD8⁺更高,CD8⁺更低（P<0.05）。与对照组相比,观察组治疗14 d后bFGF更低,SIRT1更高（P<0.05）。两组不良反应总发生率组间对比无差异（P>0.05）。结论：益肺胶囊联合乌美溴铵维兰特罗吸入粉雾剂有助于调节COPD稳定期患者血清bFGF、SIRT1水平,改善肺功能和细胞免疫功能。     

Automated Measurement of Pulmonary Emphysema and Small Airway Remodeling in Cigarette Smoke-exposed Mice

COPD is projected to be the third most common cause of mortality world-wide by 2020⁽¹⁾. Animal models of COPD are used to identify molecules that contribute to the disease process and to test the efficacy of novel therapies for COPD. Researchers use a number of models of COPD employing different species including rodents, guinea-pigs, rabbits, and dogs⁽²⁾. However, the most widely-used model is that in which mice are exposed to cigarette smoke. Mice are an especially useful species in which to model COPD because their genome can readily be manipulated to generate animals that are either deficient in, or over-express individual proteins. Studies of gene-targeted mice that have been exposed to cigarette smoke have provided valuable information about the contributions of individual molecules to different lung pathologies in COPD^(3-5). Most studies have focused on pathways involved in emphysema development which contributes to the airflow obstruction that is characteristic of COPD. However, small airway fibrosis also contributes significantly to airflow obstruction in human COPD patients⁽⁶⁾, but much less is known about the pathogenesis of this lesion in smoke-exposed animals. To address this knowledge gap, this protocol quantifies both emphysema development and small airway fibrosis in smoke-exposed mice. This protocol exposes mice to CS using a whole-body exposure technique, then measures respiratory mechanics in the mice, inflates the lungs of mice to a standard pressure, and fixes the lungs in formalin. The researcher then stains the lung sections with either Gill’s stain to measure the mean alveolar chord length (as a readout of emphysema severity) or Masson’s trichrome stain to measure deposition of extracellular matrix (ECM) proteins around small airways (as a readout of small airway fibrosis). Studies of the effects of molecular pathways on both of these lung pathologies will lead to a better understanding of the pathogenesis of COPD.     

The effects of corticosteroids on COPD lung macrophages: a pooled analysis

Background

There is large variation in the therapeutic response to inhaled corticosteroids (ICS) in COPD patients. We present a pooled analysis of our previous studies investigating the effects of corticosteroids on lung macrophages, in order to robustly determine whether corticosteroid sensitivity in COPD cells is reduced compared to controls, and also to evaluate the degree of between individual variation in drug response.

Methods

Data from 20 never smokers (NS), 27 smokers (S) and 45 COPD patients was used. Lung macropahges had been stimulated with lipopolysaccharide (LPS), with or without the corticosteroid dexamethasone, and tumour necrosis factor (TNF)-α, interleukin (IL)-6 and chemokine C-X-C motif ligand (CXCL) 8 production was measured.

Results

There was no difference in the anti-inflammatory effects of corticosteroids when comparing group mean data of COPD patients versus controls. The inhibition of TNF-α and IL-6 was greater than CXCL8. The effects of corticosteroids varied considerably between subjects, particularly at lower corticosteroid concentrations.

Conclusions

We confirm that overall corticosteroid sensitivity in COPD lung macrophages is not reduced compared to controls. The varied effect of corticosteroids between subjects suggests that some individuals have an inherently poor corticosteroid response. The limited suppression of lung macrophage derived CXCL8 may promote neutrophilic inflammation in COPD.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0260-0) contains supplementary material, which is available to authorized users.     

“Ciliophagy”

Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) associated with respiratory epithelial cell cilia shortening and impaired mucociliary clearance (MCC). The underlying cellular and molecular mechanisms for CS-associated cilia shortening have remained incompletely understood. We have previously demonstrated increased autophagy in the lungs of COPD patients; however, whether or not this process is selective for specific autophagic targets in the lung was not elucidated. Based on observations that increased morphological and biochemical indicators of autophagy correlate with cilia shortening in our models, we posited that autophagy might regulate cilia length in response to CS in the lung. We demonstrate that CS-induced cilia shortening occurs through an autophagy-dependent mechanism mediated by the deacetylase HDAC6 (histone deacetylase 6). Autophagy-impaired (Becn1^+/?, map1lc3b^?/?, or Hdac6^-/Y) mice resist CS-induced cilia shortening. Furthermore, cilia components are identified as autophagic substrates during CS exposure. Assessment of airway cilia function using a 3D MCC assay demonstrates that Becn1^+/?, map1lc3b^?/?, and Hdac6^-/Y mice or mice injected with the HDAC6 inhibitor tubastatin A are protected from CS-associated mucociliary dysfunction. We concluded that an autophagy-dependent pathway regulates cilia length during CS exposure, which identifies new pathways and targets in COPD.     

Plasma carbonyls do not correlate with lung function or computed tomography measures of lung density in older smokers

Abstract

Oxidative stress and inflammation are hallmarks of chronic obstructive pulmonary disease (COPD). A critical byproduct of oxidative damage is the introduction of carbonyl groups into amino acid residues. We hypothesize that plasma carbonyl content is inversely correlated with lung function and computed tomography (CT) measures of lung density among smokers and is elevated in COPD. Carbonyl was measured in plasma of participants aged 60 years and older by ELISA. Generalized linear and additive models were used to adjust for potential confounders. Among 541 participants (52% male, mean age 67 years, 41% current smokers), mean plasma carbonyl content was 17.9±2.9 nmol ml^?1 and mean forced expiratory volume in one second (FEV₁) was 80.7±20.9% of predicted. Plasma carbonyl content was inversely associated with FEV₁, but this relationship was largely explained by age. Multivariate analyses ruled out clinically meaningful associations of plasma carbonyl content with FEV₁, FEV₁/FVC (forced vital capacity) ratio, severity of airflow obstruction, and CT lung density. Plasma carbonyl content is a poor biomarker of oxidative stress in COPD and emphysema.     

Implication of xanthine oxidase in muscle oxidative stress in COPD patients

Objective: The aim of this study was to determine the implication of xanthine oxidase (XO) in the exercise-induced muscle oxidative stress and muscle dysfunction of these patients.

Methods: A randomized, crossover and double-blind study was conducted in nine severe COPD patients, who performed a localized quadriceps endurance test after oral treatment with allopurinol, a XO inhibitor or placebo. Redox status was studied in arterial and venous femoral blood before and after the endurance test.

Results: In placebo condition, muscle exercise resulted in a significant increase in AOPP and isoprostanes, with a significant increase in the venoarterial difference (v-a) in isoprostanes after exercise as compared with before (p<0.05). In contrast, allopurinol treatment prevented the elevation in AOPP levels and v-a isoprostanes after exercise. However, no significant improvement in quadriceps muscle endurance was observed, but allopurinol treatment seemed to preserve muscle strength properties.

Conclusion: This study demonstrates that XO is implicated in the exercise-induced muscle oxidative stress of COPD patients. Allopurinol administration seemed to improve only some muscle properties. Therefore other sources of muscle oxidative stress should be implicated in muscle dysfunction observed in these patients.