Treatment Challenges in Severe Eosinophilic Asthma: Differential Response to Anti-IL-5 and Anti-IL-5R Therapy

Severe asthma greatly affects patients’ quality of life. Major advances have occurred in the management of severe eosinophilic asthma the past few years due to the new targeted biological therapies. There are three anti-IL-5 mAbs, mepolizumab, reslizumab and benralizumab. Despite the different mechanism of blocking IL-5 the clinical effects are quite similar as randomized controlled trials and real-life studies have shown. Moreover, there are reports of responding to one after failing to respond to another anti-IL-5 therapy. Accordingly, it is challenging to explore the possible differences in the response to anti-IL-5 treatments. This might help us not only understand possible mechanisms that contribute to the resistance to treatment in this particular asthma endotype, but also to phenotype within severe eosinophilic asthma in order to treat our patients more efficiently.     

CCL4 Regulates Eosinophil Activation in Eosinophilic Airway Inflammation

Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4/MIP-1β—a specific ligand for CCR5 receptors—was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in vivo model. Furthermore, the role of CCL4 in CD69 expression—a marker of activated eosinophils—as well as the signaling pathways involved in CCL4-mediated eosinophil activation were investigated. Notably, CCL4 expression, but not CCL5, CCL11, or CCL26, was found to be significantly increased in nasal polyps from patients with ECRS associated with eosinophil infiltration as well as in BEAS-2B cells co-incubated with eosinophils. In an OVA-induced allergic mouse model, CCL4 increased eosinophil accumulation in the nasal mucosa and the bronchoalveolar lavage (BALF). Moreover, we found that CD69 expression was upregulated in CCL4-stimulated eosinophils; similarly, phosphorylation of several kinases, including platelet-derived growth factor receptor (PDGFR)β, SRC kinase family (Lck, Src, and Yes), and extracellular signal-regulated kinase (ERK), was upregulated. Further, CCR5, PDGFRβ, and/or Src kinase inhibition partially restored CCL4-induced CD69 upregulation. Thus, CCL4, which is derived from airway epithelial cells, plays a role in the accumulation and activation of eosinophils at inflammatory sites. These findings may provide a novel therapeutic target for eosinophilic airway inflammation, such as ECRS.     

Immunopathologic Role of Eosinophils in Eosinophilic Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) is a diverse chronic inflammatory disease of the sinonasal mucosa. CRS manifests itself in a variety of clinical and immunologic patterns. The histological hallmark of eosinophilic CRS (ECRS) is eosinophil infiltration. ECRS is associated with severe disease severity, increased comorbidity, and a higher recurrence rate, as well as thick mucus production. Eosinophils play an important role in these ECRS clinical characteristics. Eosinophils are multipotential effector cells that contribute to host defense against nonphagocytable pathogens, as well as allergic and nonallergic inflammatory diseases. Eosinophils interact with Staphylococcus aureus, Staphylococcal enterotoxin B, and fungi, all of which were found in the tissue of CRS patients. These interactions activate Th2 immune responses in the sinonasal mucosa and exacerbate local inflammation. Activated eosinophils were discovered not only in the tissue but also in the sinonasal cavity secretion. Eosinophil extracellular traps (EETs) are extracellular microbes trapping and killing structures found in the secretions of CRS patients with intact granule protein and filamentous chromatic structures. At the same time, EET has a negative effect by causing an epithelial barrier defect. Eosinophils also influence the local tissue microenvironment by exchanging signals with other immune cells and structural cells. As a result, eosinophils are multifaceted leukocytes that contribute to various physiologic and pathologic processes of the upper respiratory mucosal immune system. The goal of this review is to summarize recent research on the immunopathologic properties and immunologic role of eosinophils in CRS.     

Oral Corticosteroids Dependence and Biologic Drugs in Severe Asthma: Myths or Facts? A Systematic Review of Real-World Evidence

Airway inflammation represents an important characteristic in asthma, modulating airflow limitation and symptom control, and triggering the risk of asthma exacerbation. Thus, although corticosteroids represent the cornerstone for the treatment of asthma, severe patients may be dependent on oral corticosteroids (OCSs). Fortunately, the current humanised monoclonal antibodies (mAbs) benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab have been proven to induce an OCS-sparing effect in randomized controlled trials (RCTs), thus overcoming the problem of OCS dependence in severe asthma. Nevertheless, a large discrepancy has been recognized between selected patients enrolled in RCTs and non-selected asthmatic populations in real-world settings. It is not possible to exclude that the OCS-sparing effect of mAbs resulting from the RCTs could be different than the real effect resulting in clinical practice. Therefore, we performed a systematic review and correlation analysis to assess whether mAbs are effective in eliciting an OCS-sparing effect and overcoming the OCS dependence in severe asthmatic patients in real-world settings. Overall, real-world studies support the evidence that OCS dependence is a real condition that, however, can be found only in a small number of really severe asthmatic patients. In most patients, the dependence on OCS can be related to modifying factors that, when adequately modulated, may lead to a significant reduction or suspension of OCS maintenance. Conversely, in severe asthmatics in whom OCS resistance is proved by a high daily dose intake, mAbs allow reversion of the OCS dependence, leading to the suspension of OCS therapy in most patients or >50% reduction in the daily OCS dose.     

Emerging Evidence for Pleiotropism of Eosinophils

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment.     

Changes in Serum MicroRNAs after Anti-IL-5 Biological Treatment of Severe Asthma

There is currently enough evidence to think that miRNAs play a role in several key points in asthma, including diagnosis, severity of the disease, and response to treatment. Cells release different types of lipid double-membrane vesicles into the extracellular microenvironment, including exosomes, which function as very important elements in intercellular communication. They are capable of distributing genetic material, mRNA, mitochondrial DNA, and microRNAs (miRNAs). Serum miRNA screening was performed in order to analyze possible changes in serum miRNAs in 10 patients treated with reslizumab and 6 patients with mepolizumab after 8 weeks of treatment. The expression of miR-338-3p was altered after treatment (p < 0.05), although no significant differences between reslizumab and mepolizumab were found. Bioinformatic analysis showed that miR-338-3p regulates important pathways in asthma, such as the MAPK and TGF-β signaling pathways and the biosynthesis/degradation of glucans (p < 0.05). However, it did not correlate with an improvement in lung function. MiRNA-338-3p could be used as a biomarker of early response to reslizumab and mepolizumab in severe eosinophilic asthmatic patients. In fact, this miRNA could be involved in airway remodeling, targeting genes related to MAPK and TGF-β signaling pathways.     

Psychological Stress Exacerbates Inflammation of the Ileum via the Corticotropin-Releasing Hormone-Mast Cell Axis in a Mouse Model of Eosinophilic Enteritis

The effects of psychological stress on eosinophilic gastrointestinal disorders have not been elucidated. This study investigated the effects of psychological stress in a mouse model of eosinophilic enteritis (EoN). BALB/c mice were treated with ovalbumin (OVA) to create an EoN model and subjected to either water avoidance stress (WAS) or sham stress (SS). Microscopic inflammation, eosinophil and mast cell counts, mRNA expression, and protein levels of type 2 helper T cell (Th2) cytokines in the ileum were compared between groups. We evaluated ex vivo intestinal permeability using an Ussing chamber. A corticotropin-releasing hormone type 1 receptor (CRH-R1) antagonist was administered before WAS, and its effects were analyzed. WAS significantly increased diarrhea occurrence and, eosinophil and mast cell counts, and decreased the villus/crypt ratio compared to those in the SS group. The mRNA expression of CRH, interleukin IL-4, IL-5, IL-13, eotaxin-1, and mast cell tryptase β2 significantly increased, and the protein levels of IL-5, IL-13, and OVA-specific immunoglobulin E (IgE) also significantly increased in the WAS group. Moreover, WAS significantly increased the intestinal permeability. The CRH-R1 antagonist significantly inhibited all changes induced by WAS. Psychological stress exacerbated ileal inflammation via the CRH-mast cell axis in an EoN mouse model.     

Role of Short Chain Fatty Acids and Apolipoproteins in the Regulation of Eosinophilia-Associated Diseases

Eosinophils are key components of our host defense and potent effectors in allergic and inflammatory diseases. Once recruited to the inflammatory site, eosinophils release their cytotoxic granule proteins as well as cytokines and lipid mediators, contributing to parasite clearance but also to exacerbation of inflammation and tissue damage. However, eosinophils have recently been shown to play an important homeostatic role in different tissues under steady state. Despite the tremendous progress in the treatment of eosinophilic disorders with the implementation of biologics, there is an unmet need for novel therapies that specifically target the cytotoxic effector functions of eosinophils without completely depleting this multifunctional immune cell type. Recent studies have uncovered several endogenous molecules that decrease eosinophil migration and activation. These include short chain fatty acids (SCFAs) such as butyrate, which are produced in large quantities in the gastrointestinal tract by commensal bacteria and enter the systemic circulation. In addition, high-density lipoprotein-associated anti-inflammatory apolipoproteins have recently been shown to attenuate eosinophil migration and activation. Here, we focus on the anti-pathogenic properties of SCFAs and apolipoproteins on eosinophil effector function and provide insights into the potential use of SCFAs and apolipoproteins (and their mimetics) as effective agents to combat eosinophilic inflammation.     

甲基丙烯酸甲酯/丙烯酸丁酯的无皂乳液共聚

以甲基丙烯酸甲酯(MMA)和丙烯酸丁酯(BA)为主要原料,过硫酸铵为引发剂,进行无皂乳液聚合.结果表明:在不添加乳化剂的情况下,当MMA/BA=1:1、引发剂用量为0.24%、反应温度为80℃、反应时间8.0h时,所得乳液最稳定,单体转化率为81.84%,此无皂乳液对牛皮纸的粘接性比常规乳液好.     

不同生长条件对铜绿微囊藻生长的影响

目前,愈演愈烈的水体富营养化现象给水处理工艺带来了十分严峻的考验。为了深刻理解水处理工艺中主要运行条件对铜绿微囊藻生长代谢的影响,试验以藻细胞个数和胞外分泌物浓度为指标,在长达30 d的试验周期内研究了藻细胞繁殖阶段中水温、光照和振动等参数与铜绿微囊藻生长代谢变化之间的相互联系。结果发现改变水温和水力学条件对藻细胞的生长代谢有着十分重要的影响。环境条件的改变（如提高水温和增加振动频率）虽然有利于藻细胞的灭活,但也可能导致胞外分泌物含量的激增,这对水处理效果有着严重负面影响。     

藻类及其胞外分泌物对净水工艺的影响

以原水中常见蓝绿藻及其胞外分泌物的基本性质为基础,概述了目前净水工艺除藻的一般方法和原理,以及藻类及其胞外分泌物对净水工艺的影响,指出应特别关注胞外分泌物在净水处理中对消毒副产物的贡献及去除方法,采用组合工艺优化处理效果.     

分散剂聚(丙烯酸丁酯/丙烯酸)的制备和应用

比较了三种丙烯酸酯,丙烯酸共聚物的分散性,发现丙烯酸丁酯（BA）/丙烯酸（AA）具有最佳的分散性能。探讨了丙烯酸丁酯,丙烯酸共聚物制备中的单体配比、引发剂用量和反应温度对分散性的影响,同时研究了所合成共聚物的最佳使用条件。     

Properties influenced by addition of copoly (ethylene/octene) in BR–NBR blends

Abstract

The effects of copoly (ethylene/octene) (EOM) on rheological, mechanical, and cure properties and on carbon black distribution in each phase of butadiene rubber–nitrile/butadiene rubber (BR–NBR) blends have been investigated. It was found that EOM added to the blends is able to function as a plasticising agent for BR and NBR, and the plasticising efficiency of EOM is more significant in NBR than BR. With increasing EOM content, the deviation of Mooney viscosity from the additive line (interpolated values) reduces markedly. In pure components (i.e. 100 : 0 and 0 : 100), cure rate reduces and cure time increases with addition of EOM. In contrast in the blend systems, cure rate increases and cure time decreases when EOM is added. The distribution of carbon black in each phase of the blends is strongly controlled by the viscosity of each phase in the blend. The lower the phase viscosity, the greater the residual carbon black. Accordingly, dynamic mechanical thermal analysis reveals a slight shift in the glass transition temperature of the BR phase to higher temperature, compared with the NBR phase, as EOM is added. From the results obtained, it is proposed that EOM exists in the interfacial area between the two phases. However, at higher amounts of EOM, saturation of EOM at the interfacial area occurs and the excess EOM starts to migrate to the BR phase. Further increase in EOM concentration leads to saturation of EOM in the BR phase and EOM then migrates to the NBR phase.     

Eosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that “not all eosinophils are equal”. In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil “endotyping”, viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs.     

香胶树组织培养繁殖技术

将香胶树的种芽接种于不同种类与浓度的植物生长调节物MS培养基上,在同一温度、不同pH值下培养,结果表明:芽的诱导及分化培养基配方为MS+BA 0.5mg/L+NAA 0.05mg/L+蔗糖30g/L对芽的分化、增殖效果最好.培养基的最佳生根配方为:1/2MS+NAA 1.0mg/L+蔗糖30g/L+1 %AC,最佳pH值范围是5.8～6.2.     

新型高吸油树脂的制备

以丙烯酸正丁酯(BA)和甲基丙烯酸甲酯(MMA)为单体,采用改进的悬浮聚合法合成高吸油树脂。考察了单体配比、引发剂和交联剂用量、AIBN加入量及加入时间对树脂吸油性能的影响。结果表明,最佳合成条件为:单体配比BA∶MMA质量比为4∶1,引发剂BPO用量为单体质量的0.4%,交联剂N,N’-亚甲基双丙烯酰胺为单体质量的0.15%,发泡剂偶氮二异丁腈(AIBN)为单体质量的18%,在此条件下合成的树脂对甲苯的吸油率最高可达40.17 g/g,速率也明显提高。     

RTM用6421BMI树脂性能对时间的依赖性研究

主要研究了树脂传递模塑成型(RTM)用6421双马来酰亚胺(BMI)树脂在室温和低温两种不同储存条件下长期储存后的性能对时间的依赖性.用红外光谱仪检测了6421 BMI树脂体系化学状态对时间的依赖性;用差示扫描量热仪检测了6421 BMI树脂体系反应活性对时间的依赖性;用流变仪检测了6421 BMI树脂体系粘度对时间的依赖性.结果表明,储存条件对RTM用6421 BMI树脂的性能影响不大;该BMI树脂在室温和低温储存6个月后,主体化学状态未发生大的改变,其反应活性降低,但该树脂在注射温度(110℃)下至少仍有6 h的适用期.