Combined exposure to cigarette smoke and nontypeable Haemophilus influenzae drives development of a COPD phenotype in mice

Background

Cigarette smoke (CS) is the major etiologic factor of chronic obstructive pulmonary disease (COPD). CS-exposed mice develop emphysema and mild pulmonary inflammation but no airway obstruction, which is also a prominent feature of COPD. Therefore, CS may interact with other factors, particularly respiratory infections, in the pathogenesis of airway remodeling in COPD.

Methods

C57BL/6 mice were exposed to CS for 2 h a day, 5 days a week for 8 weeks. Mice were also exposed to heat-killed non-typeable H. influenzae (HK-NTHi) on days 7 and 21. One day after the last exposure to CS, mice were sacrificed and lung inflammation and mechanics, emphysematous changes, and goblet cell metaplasia were assessed. Mice exposed to CS or HK-NTHi alone or room air served as controls. To determine the susceptibility to viral infections, we also challenged these mice with rhinovirus (RV).

Results

Unlike mice exposed to CS or HK-NTHi alone, animals exposed to CS/HK-NTHi developed emphysema, lung inflammation and goblet cell metaplasia in both large and small airways. CS/HK-NTHi-exposed mice also expressed increased levels of mucin genes and cytokines compared to mice in other groups. CS/HK-NTHi-exposed mice infected with RV demonstrated increased viral persistence, sustained neutrophilia, and further increments in mucin gene and chemokine expression compared to other groups.

Conclusions

These findings indicate that in addition to CS, bacteria may also contribute to development of COPD, particularly changes in airways. Mice exposed to CS/HK-NTHi are also more susceptible to subsequent viral infection than mice exposed to either CS or HK-NTHi alone.     

Association of plasma sRAGE,but not esRAGE with lung function impairment in COPD

Rationale

Plasma soluble Receptor for Advanced Glycation End Product (sRAGE) is considered as a biomarker in COPD. The contribution of endogenous sRAGE (esRAGE) to the pool of plasma sRAGE and the implication of both markers in COPD pathogenesis is however not clear yet. The aim of the current study was therefore to measure plasma levels of esRAGE comparative to total sRAGE in patients with COPD and a control group. Further, we established the relations of esRAGE and total sRAGE with disease specific characteristics such as lung function and D_LCO, and with different circulating AGEs.

Methods

Plasma levels of esRAGE and sRAGE were measured in an 88 patients with COPD and in 55 healthy controls. FEV₁ (%predicted) and FEV₁/VC (%) were measured in both groups; D_LCO (%predicted) was measured in patients only. In this study population we previously reported that the AGE N^ϵ-(carboxymethyl) lysine (CML) was decreased, N^ϵ-(carboxyethyl) lysine (CEL) increased and pentosidine was not different in plasma of COPD patients compared to controls.

Results

Plasma esRAGE (COPD: 533.9 ± 412.4, Controls: 848.7 ± 690.3 pg/ml; p = 0.000) was decreased in COPD compared to controls. No significant correlations were observed between plasma esRAGE levels and lung function parameters or plasma AGEs. A positive correlation was present between esRAGE and total sRAGE levels in the circulation. Confirming previous findings, total sRAGE (COPD: 512.6 ± 403.8, Controls: 1834 ± 804.2 pg/ml; p < 0.001) was lower in patients compared to controls and was positively correlated FEV₁ (r = 0.235, p = 0.032), FEV₁/VC (r = 0.218, p = 0.047), and D_LCO (r = 0.308, p = 0.006). sRAGE furthermore did show a significant positive association with CML (r = 0.321, p = 0.003).

Conclusion

Although plasma esRAGE is decreased in COPD patients compared to controls, only total sRAGE showed a significant and independent association with FEV₁, FEV₁/VC and D_LCO, indicating that total sRAGE but not esRAGE may serve as marker of COPD disease state and severity.     

Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels

Background

The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel that primarily resides in airway epithelial cells. Decreased CFTR expression and/or function lead to impaired airway surface liquid (ASL) volume homeostasis, resulting in accumulation of mucus, reduced clearance of bacteria, and chronic infection and inflammation.

Methods

Expression of CFTR and the cigarette smoke metal content were assessed in lung samples of controls and COPD patients with established GOLD stage 4. CFTR protein and mRNA were quantified by immunohistochemistry and quantitative RT-PCR, respectively. Metals present in lung samples were quantified by ICP-AES. The effect of cigarette smoke on down-regulation of CFTR expression and function was assessed using primary human airway epithelial cells. The role of leading metal(s) found in lung samples of GOLD 4 COPD patients involved in the alteration of CFTR was confirmed by exposing human bronchial epithelial cells 16HBE14o- to metal-depleted cigarette smoke extracts.

Results

We found that CFTR expression is reduced in the lungs of GOLD 4 COPD patients, especially in bronchial epithelial cells. Assessment of metals present in lung samples revealed that cadmium and manganese were significantly higher in GOLD 4 COPD patients when compared to control smokers (GOLD 0). Primary human airway epithelial cells exposed to cigarette smoke resulted in decreased expression of CFTR protein and reduced airway surface liquid height. 16HBE14o-cells exposed to cigarette smoke also exhibited reduced levels of CFTR protein and mRNA. Removal and/or addition of metals to cigarette smoke extracts before exposure established their role in decrease of CFTR in airway epithelial cells.

Conclusions

CFTR expression is reduced in the lungs of patients with severe COPD. This effect is associated with the accumulation of cadmium and manganese suggesting a role for these metals in the pathogenesis of COPD.     

Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week,randomized, placebo-controlled AUGMENT COPD study

Background

Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β₂-agonist, in patients with moderate to severe COPD are presented.

Methods

In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair^®/Pressair^®)*. Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV₁ (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV₁ (FDCs versus formoterol). Secondary endpoints were change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24. Safety and tolerability were also assessed.

Results

At study end, improvements from baseline in 1-hour postdose FEV₁ were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001). Improvements in trough FEV₁ were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV₁ over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies.

Conclusions

Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo. Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01437397","term_id":"NCT01437397"}}NCT01437397.*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair^® and Genuair^® within all other licensed territories.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0123-0) contains supplementary material, which is available to authorized users.     

中期因子在相关疾病发病机制和治疗中的研究进展

中期因子(Midkine,MK),是一种分泌型肝素结合性生长因子,具有促进细胞有丝分裂、诱导细胞恶化、促进微血管生成、抑制细胞凋亡、促进炎症介质趋化、促纤溶等功能特点;经研究发现,当机体处于健康状态时中期因子除了肾脏及小肠上皮少量表达,其他部位极少表达,但机体出现疾病时,中期因子在体内的表达明显增多,如在多种恶性肿瘤、动脉粥样硬化、各类炎症、糖尿病肾病、高血压及COPD等疾病中均监测到中期因子的高表达,进一步研究发现上述疾病的发生发展与中期因子的功能特点密切相关;近年有学者利用MK在疾病发生发展中的功能特点对疾病进行治疗,特别是MK在肿瘤领域的治疗已成为研究热点,本文结合国内外的最新研究现状就MK与相关疾病的发病机制及治疗作一简要概述,并提出进一步研究的设想。     

沙美特罗/氟替卡松吸入治疗对COPD患者临床疗效及口咽部菌群和免疫功能的影响

目的 研究沙美特罗/氟替卡松吸入治疗对慢性阻塞性肺病（COPD）患者临床疗效及口咽部菌群和免疫功能的影响。方法 选取我院2015年1月至2017年12月确诊的COPD II-III级患者92例。按照随机数字表将研究对象随机分为研究组和对照组,每组46例。所有研究对象给予持续低通量吸氧、抗感染、祛痰止咳、解痉平喘等对症支持治疗,并服用盐酸氨溴索治疗。研究组在常规治疗基础上加用沙美特罗/氟替卡松干粉剂。观察患者临床疗效,记录患者肺功能指标并测定CD4+细胞、CD8+细胞、CD4+/CD8+、IgA、IgM和IgG水平。采集患者的咽拭子进行培养,计算菌落比例并鉴定种属。结果 治疗后,研究组总有效率为93.48%,明显高于对照组的80.43%,差异有统计学意义（P<0.05）。肺功能指标显示治疗后两组患者肺功能均有所上升,研究组肺功能指标水平上升幅度大于对照组（P<0.05）。治疗后研究组患者CD4+细胞和CD4+/CD8+水平高于对照组,而CD8+细胞水平低于照组,差异均有统计学意义（P<0.05）。两组患者治疗前后免疫球蛋白水平差异无统计学意义（P<0.05）。治疗后研究组患者发现9种细菌,对照组发现6种,各菌株的构成比具有一定差异。结论 沙美特罗/氟替卡松对COPD患者临床疗效显著,能有效提升肺功能,改善患者免疫功能,对口咽部菌群的影响较小,提示该吸入治疗方法值得临床应用推广。关键词：沙美特罗/氟替卡松;CODP;疗效;口咽部微生态     

慢性阻塞性肺疾病不同表型患者CAT评分与肺功能及预后的相关性分析

摘要 目的：探讨慢性阻塞性肺疾病（chronic obstructive pulmonary disease,COPD）不同表型评估测试问卷（COPD assessment test,CAT）评分与肺功能及预后的关系。方法：收集361例COPD患者临床资料、CAT评分、肺功能检查结果及肺外合并症、肺内并发症等情况,按临床表型分为肺气肿组（n=200）和支气管炎组（n=161）,分析肺气肿组200例和支气管炎组161例COPD患者CAT评分与肺功能及预后的关系。结果：肺气肿组CAT评分高于支气管炎组（P<0.05）,一秒用力呼气容积（FEV₁）占预计值百分比（FEV₁%）、FEV₁/用力肺活量（FVC）低于支气管炎组（P<0.05）,吸气分数（IC/TLC）低于支气管炎组,残总比（RV/TLC）高于支气管炎组（P<0.05）;肺气肿组肺间质性病变、肺动脉高压发生率均高于支气管炎组（P<0.05）;支气管炎、肺气肿组CAT评分均与FEV₁%、FEV₁/FVC、IC/TLC呈负相关（P<0.05）,与RV/TLC呈正相关（P<0.05）,肺气肿各参数相关度更高（P<0.05）;肺气肿组不同CAT评分患者肺间质性病变、肺动脉高压发生率比较差异有统计学意义（P<0.05）,支气管炎组不同CAT评分肺动脉高压发生率比较差异有统计学意义（P<0.05）,随CAT评分的升高,肺气肿组肺间质性病变、肺动脉高压发生率上升,支气管炎组肺动脉高压发生率上升。结论： COPD肺气肿表型CAT评分较支气管炎表型高,肺功能降低更明显,呈现肺过度通气,气流受限特点,更易并发肺间质纤维化、肺动脉高压,且与CAT评分变化密切相关。     

Autophagy and inflammation in chronic respiratory disease

Persistent inflammation within the respiratory tract underlies the pathogenesis of numerous chronic pulmonary diseases including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Chronic inflammation in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary inflammation and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting.

Abbreviations AR allergic rhinitis

AM alveolar macrophage

ATG autophagy-related

CF cystic fibrosis

CFTR cystic fibrosis transmembrane conductance regulator

COPD chronic obstructive pulmonary disease

CS cigarette smoke

CSE cigarette smoke extract

DC dendritic cell

IH intermittent hypoxia

IPF idiopathic pulmonary fibrosis

ILD interstitial lung disease

MAP1LC3B microtubule associated protein 1 light chain 3 beta

MTB Mycobacterium tuberculosis

MTOR mechanistic target of rapamycin kinase

NET neutrophil extracellular traps

OSA obstructive sleep apnea

PAH pulmonary arterial hypertension

PH pulmonary hypertension

ROS reactive oxygen species

TGFB1 transforming growth factor beta 1

TNF tumor necrosis factor