Design,synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β2-adrenoceptor agonists

A series of novel β₂-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β₂-adrenoceptor agonistic effects and high β₂/β₁-selectivity with EC₅₀ values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.     

Gastrodin relieves inflammation injury induced by lipopolysaccharides in MRC‐5 cells by up‐regulation of miR‐103

The beneficial function of gastrodin towards many inflammatory diseases has been identified. This study designed to see the influence of gastrodin in a cell model of chronic obstructive pulmonary disease (COPD). MRC‐5 cells were treated by LPS, before which gastrodin was administrated. The effects of gastrodin were evaluated by conducting CCK‐8, FITC‐PI double staining, Western blot, qRT‐PCR and ELISA. Besides this, the downstream effector and signalling were studied to decode how gastrodin exerted its function. And dual‐luciferase assay was used to detect the targeting link between miR‐103 and lipoprotein receptor‐related protein 1 (LRP1). LPS induced apoptosis and the release of MCP‐1, IL‐6 and TNF‐α in MRC‐5 cells. Pre‐treating MRC‐5 cells with gastrodin attenuated LPS‐induced cell damage. Meanwhile, p38/JNK and NF‐κB pathways induced by LPS were repressed by gastrodin. miR‐103 expression was elevated by gastrodin. Further, the protective functions of gastrodin were attenuated by miR‐103 silencing. And LRP1 was a target of miR‐103 and negatively regulated by miR‐103. The in vitro data illustrated the protective function of gastrodin in LPS‐injured MRC‐5 cells. Gastrodin exerted its function possibly by up‐regulating miR‐103 and modulating p38/JNK and NF‐κB pathways.     

合并慢性气道疾病的ARDS临床特征及预后影响因素研究

目的:探讨急性呼吸窘迫综合征(ARDS)合并慢性气道疾病患者的临床特征及影响预后的因素。方法:167例ARDS患者根据并发症发生情况分为对照组(单纯性ARDS组,A组,n=39)及观察组(ARDS合并慢性气道疾,B组,n=49,C组,n=41,D组,n=38),比较各组患者一般情况、临床特征、生化指标、治疗方式及预后状况,通过logistic回归分析ARDS合并慢性气道疾病患者预后的影响因素。结果:观察组(B、C、D组)年龄、中性粒细胞、IL-6、IL-8、TNF-α、白蛋白、pro-BNP、乳酸、氧合指数、住院时间、住院费用与对照组(A组)比较差异有统计学意义,P0.05;128例ARDS合并慢性气道疾病患者中死亡76例,好转52例,病死率59.38%;单因素分析结果显示,观察组(B、C、D组)患者中临床结局好转患者与死亡患者比较,白细胞、淋巴细胞、CRP、TNF-α、IL-8、降钙素、肌酐、pro-BNP、氧合指数、住院费用、机械通气时间、抗生素数量差异有统计学意义,P0.05;通过多因素logistic回归分析发现肌酐是影响ARDS合并慢性气道疾病的潜在危险因素,氧合指数为保护因素,P0.05。结论:ARDS合并慢性气道疾病的能量代谢紊乱程度可能较单纯ARDS加重,且两者炎性特征不同。肌酐、氧合指数是影响ARDS合并慢性气道疾病的重要影响因素。     

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。     

Bi PAP呼吸机无创通气联合氧气驱动雾化吸入对慢阻肺合并呼吸衰竭的疗效

摘要 目的：研究Bi PAP呼吸机无创通气以及氧气驱动雾化吸入联用对慢性阻塞性肺疾病（慢阻肺）合并呼吸衰竭的疗效。方法：选择2016年12月～2018年12月我院的121例慢阻肺合并呼吸衰竭患者,随机分为两组。对照组采用Bi PAP呼吸机无创通气疗法,观察组联合氧气驱动雾化吸入布氨溴索和地奈德混悬液。比较两组的呼吸频率、血气指标和心率;血清肺表面活性相关蛋白D(Pulmonary surfactant related protein,SP-D)以及部活化调节趋化因子(PARC/CCL18)水平、肺功能。结果：观察组的有效率明显高于对照组(P<0.05);治疗后,两组的呼吸频率、血气指标和心率明显改善(P<0.05),且观察组的呼吸频率、血气指标和心率明显优于对照组(P<0.05);治疗后,两组的血清PARC/CCL18 以及SP-D水平均明显降低(P<0.05),且观察组的血清PARC/CCL18 以及SP-D水平明显低于对照组(P<0.05);治疗后,两组的FEV₁%、呼吸困难指数以及FEV₁/FVC明显改善(P<0.05),且观察组的FEV₁%、呼吸困难指数以及FEV₁/FVC明显优于对照组(P<0.05)。结论：Bi PAP呼吸机无创通气以及氧气驱动雾化吸入联用能改善慢阻肺合并呼吸衰竭的血气指标、生命体征和肺功能,降低血清 PARC/CCL18 以及SP-D水平。     

High-resolution mass spectrometry proteomics for the identification of candidate plasma protein biomarkers for chronic obstructive pulmonary disease

Although cigarette smoking is recognized as the most important cause of chronic obstructive pulmonary disease (COPD), the pathophysiological mechanisms underlying the lung function decline are not well understood. Using off-line strong cation exchange fractionation with RP-LC-ESI-MS/MS and robust database searching, 1758 tryptic peptides were identified in plasma samples from cigarette smokers. Using two statistical approaches, 30 peptides were identified to be associated with the annualized rate of lung function decline over 5 years among smokers with COPD characterized as having rapid (n?=?18) or slow (n?=?18) decline and 18 smokers without COPD. The identified peptides belong to proteins that are involved in the complement or coagulation systems or have antiprotease or metabolic functions. This research demonstrates the utility of proteomic profiling to improve the understanding of molecular mechanisms involved in cigarette smoking-related COPD by identifying plasma proteins that correlate with decline in lung function.     

The drug efflux pump Pgp1 in pro-inflammatory lymphocytes is a target for novel treatment strategies in COPD

Background

Pro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD. NKT-like and NK cells are effector lymphocytes that we have also shown to be major sources of pro-inflammatory cytokines and granzymes. P-glycoprotein 1 (Pgp1) is a transmembrane efflux pump well characterised in drug resistant cancer cells. We hypothesized that Pgp1 would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNγ, TNFα and granzyme B. We further hypothesized that treatment with cyclosporine A, a Pgp1 inhibitor, would render cells more sensitive to treatment with corticosteroids.

Methods

Pgp1, granzyme B, IFNγ and TNFα expression were measured in peripheral blood T, NK and NKT-like cells from COPD patients and control subjects (± cyclosporine A and prednisolone) following in vitro stimulation and results correlated with uptake of efflux dye Calcein-AM using flow cytometry.

Results

There was increased Pgp1 expression by peripheral blood T, NKT-like and NK cells co-expressing IFNγ, TNFα and granzyme B in COPD patients compared with controls (e.g. %IFNγ/Pgp1 T, NKT-like, NK for COPD (Control): 25(6), 54(27), 39(23)). There was an inverse correlation between Pgp1 expression and Calcein-AM uptake. Treatment with 2.5 ng/ml cylosporin A and10^-6 M prednisolone resulted in synergistic inhibition of pro-inflammatory cytokines in Pgp1 + cells (p < 0.05 for all).

Conclusions

Treatment strategies that target Pgp1 in T, NKT-like and NK cells may reduce systemic inflammatory mediators in COPD and improve patient morbidity.     

Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD

Background

Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure.

Methods

Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM.

Results

The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure.

Conclusions

These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.     

Inhibition of LPS-induced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist

Background

Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic response in the airways of healthy volunteers that can be quantified in induced sputum. Chemokines, such as CXCL1 and CXCL8, play an important role in neutrophilic inflammation in the lung through the activation of CXCR2 and small molecule antagonists of these receptors have now been developed. We investigated the effect of AZD8309, a CXCR2 antagonist, compared with placebo on LPS-induced inflammation measured in sputum of healthy volunteers.

Methods

Twenty healthy subjects were randomized in a double-blind placebo-controlled, cross-over study. AZD8309 (300 mg) or placebo was dosed twice daily orally for 3 days prior to challenge with inhaled LPS and induced sputum was collected 6 h later.

Results

Treatment with AZD8309 showed a mean 77% reduction in total sputum cells (p < 0.001) and 79% reduction in sputum neutrophils (p < 0.05) compared with placebo after LPS challenge. There was also a reduction in neutrophil elastase activity (p < 0.05) and CXCL1 (p < 0.05) and trends for reductions in sputum macrophages (47%), leukotriene B₄ (39%) and CXCL8 (52%).

Conclusions

AZD8309 inhibited LPS-induced inflammation measured in induced sputum of normal volunteers, indicating that this treatment may be useful in the treatment of neutrophilic diseases of the airways, such as COPD, severe asthma and cystic fibrosis.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00860821","term_id":"NCT00860821"}}NCT00860821.