Role of interleukin-17F in chronic inflammatory and allergic lung disease

IL-17 family members belong to a distinct category of cytokines that coordinate local tissue inflammation by inducing the release of pro-inflammatory and neutrophil-mobilizing cytokines. The importance of the IL-17 family in inflammatory and autoimmune disease is becoming increasingly apparent. IL-17F is a recently discovered member of the IL-17 family that has a number of biological activities through induction of various cytokines, chemokines, and mediators. IL-17A, the founding member of the IL-17 family, and IL-17F are produced by several inflammatory cells, including activated T cells, in response to infectious and antigenic stimuli. Overexpression of IL-17A or IL-17F in the lungs results in induction of CXC chemokines and neutrophil recruitment. In a case-control study of 1125 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL17F gene was shown to be associated with asthma and chronic obstructive pulmonary disease (COPD). Functionally, this variant failed to induce cytokines and chemokines, and interestingly, was able to antagonize the activity of wild-type IL-17F. These results provide an experimental basis for the observed genetic association with chronic inflammatory lung diseases, and also suggest the potential therapeutic utility of this antagonistic variant of IL-17F. Given that asthma and COPD are complex diseases involving a number of genetic and environmental factors, the genetic impact of IL-17F H161R with regard to the development of chronic airway inflammation likely varies among individuals with different genetic backgrounds and environmental exposures.     

Role of intercellular adhesion molecule-1 in a murine model of toluene diisocyanate-induced asthma

BACKGROUND: Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) are thought to contribute to the airway inflammation and airway hyper-responsiveness (AHR) of allergic asthma. Some differences from allergic asthma have been noted, including airway neutrophilia, and the involvement of ICAM-1 in toluene diisocyanate (TDI) asthma is currently unclear. OBJECTIVE: We utilized mice lacking ICAM-1 expression (ICAM-1(-/-)) to investigate the role of ICAM-1 in airway inflammation and AHR in TDI-induced asthma. METHODS: Male C57BL/6J mice (ICAM-1(+/+)) and ICAM-1(-/-) mice were intranasally sensitized to TDI solution or solvent alone. Airway inflammation, AHR and cytokine secretion were assessed 24 h after challenge by TDI or solvent. The production of antigen-specific IgG and IgE by TDI sensitized and non-sensitized mice was determined. RESULTS: TDI challenge to ICAM-1(+/+) mice induced an increase in airway inflammatory cell numbers, AHR and cytokine secretion of TNF-alpha, macrophage inflammatory protein-2 (MIP-2), IL-4, IL-5 and IFN-gamma into the bronchoalveolar lavage fluid. All these pathophysiological changes were reduced in ICAM-1(-/-) mice. Serum levels of TDI-specific IgG and IgE of ICAM-1(-/-) and ICAM-1(+/+) mice were comparable. CONCLUSION: These results suggest that ICAM-1 plays an essential role in airway inflammation and AHR in TDI-induced asthma.     

肺表面活性蛋白A在皮质类固醇调节哮喘小鼠树突细胞共刺激分子表达中的作用

目的 研究皮质类固醇激素调节小鼠哮喘模型树突细胞表面共刺激分子表达的机制，以及肺表面活性蛋白A（SP-A）在其调节中的作用。方法 BALB/c小鼠30只，分为3组：哮喘组，采用卵蛋白（OVA）致敏和激发；对照组，以生理盐水代替OVA；治疗组，每次OVA激发后10min，腹腔注射地塞米松01mg。用免疫组化法检测SP-A在肺内的表达情况。采用Leica DM Snk软件进行图像采集，并用Qwin软件计算小气道内棕色区域面积，取平均值，进行统计分析。分离培养脾脏树突细胞，用流式细胞仪（FACS）检测树突细胞表面共刺激分子CD80的表达变化。结果 哮喘组肺组织表现为嗜酸性细胞及淋巴细胞浸润为主的炎症变化，治疗组和对照组无此变化。哮喘组的SP-A表达明显低于对照组和治疗组（P〈0．01），CD80的表达率明显高于治疗组（P〈0.01）；哮喘组小气道内SP-A表达与树突细胞CD80阳性率呈负相关（r=-0．907，P〈0．01）。结论 皮质类固醇对小鼠哮喘模型的肺表面活性蛋白有明显的保护作用，可通过激发肺表面活性蛋白抑制树突细胞表面共刺激分子CD80的表达。     

The effectiveness of intranasal corticosteroids in combined allergic rhinitis and asthma syndrome

Background Allergic rhinitis (AR) and asthma often coexist and may represent two manifestations of the same disease recently named combined AR and asthma syndrome (CARAS). Aim To review the common pathophysiology of combined AR and asthma and to investigate the efficacy of intranasal corticosteroids (INCS). Methods Medline was used to identify articles relevant to mechanisms. A Cochrane systematic review was performed to assess the efficacy of INCS in CARAS. Results There is cross‐talk, evidence of a common inflammatory response in both sites, linked by a systemic component. The efficacy of anti‐inflammatory INCS on asthma outcomes was assessed in a systematic review of 12 randomized controlled trials involving 425 subjects. After INCS there were non‐significant trends for improvement in asthma symptom score (standardized mean difference (SMD) of 0.61; P=0.07), forced expiratory volume in 1 s (SMD of 0.31; P=0.08), and morning peak expiratory flow (weighted mean difference of 36.51; P=0.06). There was no impact on methacholine airways responsiveness (SMD of ?0.20; P=0.4). The review identified two promising new treatment options in united airway disease such as INCS as monotherapy in rhinitis and mild asthma, and a combined intranasal and intrabronchial corticosteroid (IBCS) deposition technique. Conclusion Common mucosal inflammatory responses occur in CARAS. This systematic review shows trends for a benefit of INCS in CARAS, but recognizes that more research is needed. At this stage, the current best practice is to treat asthma conventionally with IBCS with or without β₂‐agonist and to add INCS to improve specific rhinitis symptoms.     

Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses

BACKGROUND : Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%. OBJECTIVE : To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only. METHODS : Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge. RESULTS : TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia. CONCLUSION : We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.     

Polymorphism of the mast cell chymase gene (CMA1) promoter region: lack of association with asthma but association with serum total immunoglobulin E levels in adult atopic dermatitis

BACKGROUND: Mast cell chymase has the potential to be an important mediator of inflammation and remodelling in the asthmatic lung. Previous studies have examined association between promoter polymorphism of the chymase gene (CMA1) and allergic phenotypes but the significance of this polymorphism is unclear. We have examined association of a CMA1 variant in relation to asthma in a large UK Caucasian family cohort. METHODS: A polymorphism of the CMA1 gene promoter (-1903G/A) was genotyped in 341 asthmatic families and in 184 non-asthmatic adults recruited from the UK PCR-RFLP based genotyping. Association with asthma diagnosis, atopy, specific and total IgE, and atopy and asthma severity was examined. RESULTS: Case-control studies did not reveal a significant difference in allele frequency between asthmatics and controls. A significant association was found between CMA1 genotypes and total IgE levels in subjects with self-reported eczema that remained significant after correction for multiple testing (median total serum IgE GG 297 kU/L, GA 144 kU/L, AA 48.4 kU/L, Pc=0.0032). CONCLUSION: These data suggest that CMA1 promoter polymorphism does not contribute to asthma susceptibility or severity but may be involved in regulating IgE levels in patients with eczema.     

人胎盘脂多糖辅助治疗支气管哮喘临床疗效观察

目的观察人胎盘脂多糖辅助治疗儿童支气管哮喘的临床疗效。方法将我院91例支气管哮喘患儿随机分成2组,治疗组46例,采用综合疗法,发作期应用沙丁胺醇、普米克令舒、氨茶碱治疗,缓解期肌内注射人胎盘脂多糖、气雾吸入倍氯米松;对照组45例,发作期用沙丁胺醇、普米克令舒、氨茶碱治疗,缓解期气雾吸入倍氯米松。结果治疗2周后治疗组、对照组对改善喘息、咳嗽症状比较,差异有显著性意义(P<0.05)。随访1年,治疗组复发率与对照组比较,差异有显著性意义(P<0.05)。结论人胎盘脂多糖辅助治疗支气管哮喘疗效确切,复发率低,值得临床推广应用。     

Addition of Transdermal or Inhaled Long-Acting β 2-Agonists in Adult Asthmatic Patients Treated with Inhaled Corticosteroids: Switchover Study from Tulobuterol Patch to Salmeterol Dry Powder Inhaler

Sixty-four patients with persistent asthma receiving 200 to 800 μ g of fluticasone propionate daily were enrolled in this switchover study. The patients applied a tulobuterol patch 2 mg every 24 hours for 4 weeks followed by inhalation of salmeterol 100 μ g bid for 4 weeks. The mean values for morning and evening peak expiratory flow improved significantly compared with baseline during the 4 weeks of tulobuterol patch treatment. Further improvement was seen on switching to salmeterol treatment, which was significant even in the first week, and continued until the final week of the study. Use of salmeterol alone resulted in a significant increase in the percentage of forced expiratory volume in 1 second %FEV1 from baseline, with 51% of patients feeling that the treatment was effective (vs. 37% on tulobuterol). These data suggest that salmeterol can achieve better control in asthmatic patients after switching from using tulobuterol patches.     

Low-dose endotoxin in allergic asthmatics: effect on bronchial and inflammatory response to cat allergen

BACKGROUND: Endotoxin was proposed to increase the severity of asthma. Endotoxin levels greatly differ according to settings. In domestic environments, airborne concentrations may be dramatically low compared with levels reported in occupational settings. OBJECTIVE: Our first objective was therefore to assess the effect of inhalation of low-level lipopolysaccharide (LPS) on the immediate and late-phase asthmatic bronchial response. Our second objective was to evaluate the effect of exposure to LPS on the local and systemic inflammatory response. METHODS: Nineteen asthmatics sensitized to cat underwent on two separate occasions a bronchial challenge test to cat allergen (cat BCT) preceded randomly by a pre-exposure to either saline or LPS (2 microg). Methacholine challenge test was performed 24 h before exposure to LPS or saline. The Borg scale for dyspnoea and lung function were recorded before and after exposure to LPS or saline, and before and after cat BCT. Induced sputum and blood samples were collected before and after cat BCT, and analysed for cell counts and eosinophil cationic protein (ECP) levels. RESULTS: Inhalation of 2 microg LPS did not induce any changes in forced expiratory volume in 1 s (FEV1), peak expiratory flow (PEF), FEF 25-75 and Borg scale of dyspnoea. It neither modified Fel d 1 PD20 (45.03 ng as compared with 87.03; P=0.42). As well, there was no significant difference in late-phase reaction. Pre-exposure to LPS did not influence eosinophil counts or ECP levels in blood and sputum. CONCLUSION: Our study demonstrated that pre-exposure to LPS at low levels, which may be encountered in domestic environment, had no significant effect on the immediate and late-phase bronchial response to cat allergen. It neither modified local and systemic eosinophilic inflammation.