Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma

Background

The low toxicity of perfluorocarbons (PFCs), their high affinity for respiratory gases and their compatibility with lung surfactant have made them useful candidates for treating respiratory diseases such as adult respiratory distress syndrome. We report results for treating acute allergic and non-allergic bronchoconstriction in sheep using S-1226 (a gas mixture containing carbon dioxide and small volumes of nebulized perflubron). The carbon dioxide, which is highly soluble in perflubron, was used to relax airway smooth muscle.

Methods

Sheep previously sensitized to house dust mite (HDM) were challenged with HDM aerosols to induce early asthmatic responses. At the maximal responses (characterised by an increase in lung resistance), the sheep were either not treated or treated with one of the following; nebulized S-1226 (perflubron + 12% CO₂), nebulized perflubron + medical air, 12% CO₂, salbutamol or medical air. Lung resistance was monitored for up to 20 minutes after cessation of treatment.In additional naïve sheep, a segmental bronchus was pre-contracted with methacholine (MCh) and treated with nebulized S-1226 administered via a bronchoscope catheter. Subsequent bronchodilatation was monitored by real time digital video recording.

Results

Treatment with S-1226 for 2 minutes following HDM challenge resulted in a more rapid, more profound and more prolonged decline in lung resistance compared with the other treatment interventions. Video bronchoscopy showed an immediate and complete (within 5 seconds) re-opening of MCh-constricted airways following treatment with S-1226.

Conclusions

S-1226 is a potent and rapid formulation for re-opening constricted airways. Its mechanism(s) of action are unknown. The formulation has potential as a rescue treatment for acute severe asthma.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0098-x) contains supplementary material, which is available to authorized users.     

Allergic diseases and asthma in the family predict the persistence and onset-age of asthma: a prospective cohort study

BackgroundFamily history of asthma and other allergic diseases have been linked to the risk of childhood asthma previously, but little is known about their effect on the age-of-onset and persistency of asthma until young adulthood.MethodsWe assessed the effect of the family history of asthma and allergic diseases on persistent vs. transient, and early- vs. late-onset persistent asthma in The Espoo Cohort Study 1991–2011, a population-based cohort study of 1623 subjects (follow-up rate 63.2%). The determinants were any family history (any parent or sibling); maternal; paternal; siblings only; parents only; and both siblings and parents. Analyses were conducted separately for asthma and allergic diseases while taking the other disease into account as a confounding factor. The outcomes were persistent, transient, early-onset persistent (<13 years) and late-onset persistent asthma. Adjusted risk ratios (RR) were calculated applying Poisson regression. Q-statistics were used to assess heterogeneity between RRs.ResultsFamily history was associated with the different subtypes but the magnitude of effect varied quantitatively. Any family history of asthma was a stronger determinant of persistent (adjusted RR = 2.82, 95% CI 1.99-4.00) than transient asthma (1.65, 1.03-2.65) (heterogeneity: P = 0.07) and on early-onset than late-onset persistent asthma. Also any family history of allergic diseases was a stronger determinant of persistent and early-onset asthma. The impact of paternal asthma continued to young adulthood (early-onset: 3.33, 1.57-7.06 vs. late-onset 2.04, 0.75-5.52) while the influence of maternal asthma decreased with age (Early-onset 3.94, 2.11-7.36 vs. Late-onset 0.88, 0.28-2.81). Paternal allergic diseases did not follow the pattern of paternal asthma, since they showed no association with late-onset asthma. Also the effect estimates for other subtypes were lower than in other hereditary groups (persistent 1.29, 0.75-2.22 vs. transient 1.20, 0.67-2.15 and early-onset 1.86, 0.95-3.64 vs. late-onset 0.64, 0.22-1.80).ConclusionsFamily history of asthma and allergic diseases are strong determinants of asthma, but the magnitude of effect varies according to the hereditary group so that some subtypes have a stronger hereditary component, and others may be more strongly related to environmental exposures. Our results provide useful information for assessing the prognosis of asthma based on a thorough family history.     

Allergic airway inflammation induces the migration of dendritic cells into airway sensory ganglia

Background

A neuroimmune crosstalk between dendritic cells (DCs) and airway nerves in the lung has recently been reported. However, the presence of DCs in airway sensory ganglia under normal and allergic conditions has not been explored so far. Therefore, this study aims to investigate the localisation, distribution and proliferation of DCs in airway sensory ganglia under allergic airway inflammation.

Methods

Using the house dust mite (HDM) model for allergic airway inflammation BALB/c mice were exposed to HDM extract intranasally (25 μg/50 μl) for 5 consecutive days a week over 7 weeks. With the help of the immunohistochemistry, vagal jugular-nodose ganglia complex (JNC) sections were analysed regarding their expression of DC-markers (MHC II, CD11c, CD103), the neuronal marker PGP 9.5 and the neuropeptide calcitonin gene-related peptide (CGRP) and glutamine synthetase (GS) as a marker for satellite glia cells (SGCs). To address the original source of DCs in sensory ganglia, a proliferation experiment was also carried in this study.

Results

Immune cells with characteristic DC-phenotype were found to be closely located to SGCs and vagal sensory neurons under physiological conditions. The percentage of DCs in relation to neurons was significantly increased by allergic airway inflammation in comparison to the controls (HDM 51.38 ± 2.38% vs. control 28.16 ± 2.86%, p < 0.001). The present study also demonstrated that DCs were shown to proliferate in jugular-nodose ganglia, however, the proliferation rate of DCs is not significantly changed in the two treated animal groups (proliferating DCs/ total DCs: HDM 0.89 ± 0.38%, vs. control 1.19 ± 0.54%, p = 0.68). Also, increased number of CGRP-positive neurons was found in JNC after allergic sensitisation and challenge (HDM 31.16 ± 5.41% vs. control 7.16 ± 1.53%, p < 0.001).

Conclusion

The present findings suggest that DCs may migrate from outside into the ganglia to interact with sensory neurons enhancing or protecting the allergic airway inflammation. The increase of DCs as well as CGRP-positive neurons in airway ganglia by allergic airway inflammation indicate that intraganglionic DCs and neurons expressing CGRP may contribute to the pathogenesis of bronchial asthma. To understand this neuroimmune interaction in allergic airway inflammation further functional experiments should be carried out in future studies.     

Pharmacological modulation of reactive oxygen species (ROS) improves the airway hyperresponsiveness by shifting the Th1 response in allergic inflammation induced by ovalbumin

Asthma is an allergic inflammation driven by the Th2 immune response with release of cytokines such as IL-4 and IL-13, which contribute to the airflow limitations and airway hyperresponsiveness (AHR). The involvement of oxidative stress in this process is well-established, but the specific role of the superoxide anion and nitric oxide in asthma are poorly understood. Thus, the aim of this study was to investigate the mechanisms underlying the superoxide anion/nitric oxide production and detoxification in a murine asthma model. BALB/c male mice were sensitised and challenged with ovalbumin (OVA). Pretreatments with either apocynin (14?mg/kg) or allopurinol (25?mg/kg) (superoxide anion synthesis inhibitors), aminoguanidine (50?mg/kg) (nitric oxide synthesis inhibitor) or diethyldithiocarbamate (100?mg/kg) (superoxide dismutase inhibitor) were performed 1?h before the challenge. Our data showed that apocynin and allopurinol ameliorated AHR and reduced eosinophil peroxidase, as well as IL-4 and IL-13 levels. Apocynin also abrogated leukocyte peribronchiolar infiltrate and increased IL-1β secretion. Aminoguanidine preserved lung function and shifted the Th2 to the Th1 response with a reduction of IL-4 and IL-13 and increase in IL-1β production. Diethyldithiocarbamate prevented neither allergen-induced AHR nor eosinophil peroxidase (EPO) generation. All treatments protected against oxidative damage observed by a reduction in TBARS levels. Taken together, these results suggest that AHR in an asthma model can be avoided by the down-regulation of superoxide anion and nitric oxide synthesis in a mechanism that is independent of a redox response. This down-regulation is also associated with a transition in the typical immunological Th2 response toward the Th1 profile.     

孟鲁斯特纳联合玉屏风颗粒治疗小儿过敏性鼻炎的临床疗效

目的:探讨孟鲁斯特纳联合玉屏风颗粒治疗小儿过敏性鼻炎患者的临床疗效及安全性。方法:选取于我院进行治疗的小儿过敏性鼻炎患者60例,根据电脑生成的随机数字表将所有患者随机分为实验组与对照组,每组各30例。对照组患者给予孟鲁斯特纳进行治疗,实验组患者在对照组的基础上联合使用中药制剂玉屏风颗粒进行治疗。比较两组患者治疗前后血清免疫球蛋白A(IgA)、免疫球蛋白G(IgG)、免疫球蛋白E(IgE)、白介素6(IL-6)、白介素17(IL-17)及白介素23(IL-23)水平,并对两组患者治疗过程中的不良反应进行记录,评价两组患者的临床疗效。结果:与治疗前相比,两组患者治疗后的血清IgA、IgG水平均升高(P0.05),IgE、IL-6、IL-17及IL-23水平均降低(P0.05);与对照组相比,实验组患者血清IgA、IgG水平及临床总有效率较高(P0.05),IgE、IL-6、IL-17、IL-23水平及不良反应发生率较低(P0.05)。结论:孟鲁斯特纳联合玉屏风颗粒治疗小儿过敏性鼻炎安全有效,可能与其影响机体血清IgA、IgG、IgE、IL-6、IL-17及IL-23水平有关。     

Synthesis and biological evaluation of peptide-derived TSLP inhibitors

Thymic stromal lymphopoietin (TSLP) is a type II cytokine which is associated with most inflammatory allergic disorders in humans. It is produced mainly by epithelial cells with important role in the development of chronic inflammatory diseases by activating T-helper cell type-2 (T_H2) pathways. In this study, a total of 16 peptides were prepared by solid phase peptide synthesis based on amino acid sequences of the interface between TSLP and TSLP receptor. Their TSLP inhibition activities were determined by ELISA assay. Among them, three peptides (6?8) exhibited >50% inhibition at concentration of 0.3 mM. They can be used as hit compounds for developing peptide-based TSLP inhibitors.     

肠道微生物与过敏性疾病关系研究进展

目前,过敏性疾病的防治主要依赖于使用抗生素,然而抗生素的滥用已造成了严重的危害。近年来随着肠道微生物相关研究的不断深入以及人们对过敏性疾病的日益关注与重视,肠道微生物与过敏性疾病间的关系逐渐受到科学家们的关注。调整肠道菌群结构可能为过敏性疾病的防治提供新的思路。目前对肠道微生物与过敏性疾病间的相关性报道相对较少且未有深层次的剖析。本文总结了关于肠道微生物与过敏性疾病关系的研究起源、发展与现状,旨在为过敏性疾病的防治提供新策略。     

川芎白芷对过敏性皮炎模型的血流变及炎性因子表达影响的实验研究

摘要 目的：从皮下血流变和炎性因子表达的角度，研究川芎白芷对过敏性皮炎组织的干预作用。方法：将60只雄性纯白豚鼠随机分为正常组、模型组、白芷组、川芎组、川芎白芷合用组和阳性药组。除正常组外，其余各实验组均使用2.4-二硝基氯苯法建立变应性接触性皮下炎症模型。建模成功后每组按设计分别在致炎各处涂抹各组药物，末次给药4 h后使用激光多普勒血流成像系统检测各组豚鼠患侧耳血流变化，取各实验组豚鼠耳组织，制备HE染色的病理切片，并使用酶联免疫吸附试验(ELISA)法检测耳组织中炎症指标因子IL-1β、TNF-α、LTB4、LTD4、PGE2和PGD2的水平。结果：与正常组比，致敏模型组的耳枝干与末端血管血流急剧增加，各给药组与模型组比较耳血管血流变明显降低，其中川芎白芷合用对炎症组织枝干血管血流影响最显著；模型的相关炎性因子水平均显著升高，各给药组炎症因子指标显著下降，LTB4、LTD4、PGD2、PGE2水平下降。川芎组与白芷组相比，抑制白细胞三烯指标LTB4、LTD4的作用更显著，白芷在IL-1β、IL-8作用较明显，川芎白芷合用组的作用优于川芎和白芷单用组。结论：川芎白芷对急性皮下炎症模型有治疗作用，可抑制组织中炎症反应，减少前列腺素类及白三烯类物质的释放，改善炎症引起的血流变反应。川芎白芷对皮下急性炎症的作用机制有差别，在抑制白细胞三烯类和白介素类炎症介质过程中有协同配伍效果。     

Histamine H1 receptor gene polymorphism acts as a biological indicator of the prediction of therapeutic efficacy in patients with allergic rhinitis in the Chinese Han population

H1-antihistamine has been shown to be effective in treating patients with allergic rhinitis (AR), but its mechanism is still uncertain. We investigated effects of histamine H1 receptor (HRH1) gene polymorphisms on the efficacy of oral H1-antihistamine in perennial patients with AR caused by mites in the Chinese Han population for the first time. A total of 224 Han Chinese patients with AR and 165 Han Chinese healthy volunteers were selected. Genotype and allele frequency distribution of −17C/T in HRH1 gene in patients with AR, serum levels of eosinophil cationic protein (ECP), total immunoglobulin E (IgE), and specific IgE were detected. The clinical symptoms of patients with AR were evaluated with visual analogue scale (VAS). Direct counting method was applied to calculate genotype and allele frequencies. Higher levels of serum ECP and total IgE were shown in the AR group. Moreover, patients with CT, TT, or CT+TT genotype increased the risk of AR incidence in the in the −17C/T site of HRH1, and CC genotype and CT+TT genotype were associated with gender, asthma, VAS score, total IgE level, and specific IgE level in patients with AR. In addition, oral administration of H1-antihistamines improves clinical symptoms of patients with AR. At last, patients with the CC genotype showed the increased efficacy of H1-antihistamines in patients with AR. Our study provides evidence that HRH1 gene polymorphisms may correlate with oral H1-antihistamine efficacy for the treatment of patients with AR, which can be used as a biological indicator of the prediction of therapeutic efficacy of patients with AR.