Inflammation-allergy and prostanoids. (2). The role of prostanoids in allergic inflammation

Allergic inflammation is orchestrated by mainly antigen-specific CD4+ T cells, eosinophils and mast cells, which is a characteristic feature of bronchial asthma, rhinitis and atopic dermatitis. Prostanoids are one of the arachidonic metabolites, which are produced by a variety of inflammatory cells upon stimulation and are thought to be involved in the pathogenesis of diseases as well as the regulation of homeostasis. We investigated the role of a prostanoid, prostaglandin D2 (PGD2), in the pathogenesis of allergic bronchial asthma using its receptor, DP, gene-deficient mice. We found that the disruption of the DP gene attenuated the allergen-induced airway eosinophilic inflammation, Th2 type cytokine production and bronchial hyperresponsiveness to cholinergic stimuli, suggesting that PGD2 is an important mediator of allergic asthma. In contrast, the treatment of non-steroidal anti-inflammatory agents, which are known to be inhibitors of cyclooxygenases, did not inhibit or instead exaggerated these responses in asthmatics or experimental animal models, indicating that there are regulatory prostanoids in allergic inflammation. Recently, strategies of gene manipulation such as the "knockout" or "transgenic" techniques are important means to understand the role of a certain functional molecule. These approaches and the development of their antagonists/inhibitors could help us to understand the function of prostanoids in the pathophysiology of allergic disorders.     

Effects of saiboku-to on dual-phase bronchoconstriction in asthmatic guinea pigs.

In recent years, bronchial asthma has come to be regarded pathologically as a chronic inflammatory disease of the respiratory tract. Inhalational steroids and antiinflammatory drugs are recognized as being effective against bronchial asthma. In this study, the effects of Saiboku-to, a Chinese herbal (Kampo) formulation, were investigated on asthmatic guinea pigs sensitized to ovalbumin (OA). Following 7-day administration of Saiboku-to (500 micrograms/kg), the late asthmatic response (LAR) to an antigen challenge was found to be inhibited. The number of eosinophils in fluid obtained by bronchoalveolar lavage (BAL) 4 h after antigen challenge was decreased while the infiltration of eosinophils and T-lymphocytes into the lung parenchyma was inhibited. These findings suggest that Saiboku-to has the potential to become a useful drug in the treatment of bronchial asthma.     

The Role of Lymphocytes in the Pathogenesis of Asthma and COPD

Asthma and chronic obstructive pulmonary disease (COPD) are two different inflammatory disorders of the lungs which share a common functional abnormality, i.e. airflow limitation [1,2]. In asthma, airflow limitation is largely reversible, either spontaneously or with treatment, and does not progress in most cases [1]. On the other hand, airflow limitation in COPD is usually progressive and poorly reversible [2]. In asthma, the chronic inflammation causes an associated increase in airway responsiveness to a variety of stimuli, leading to recurrent episodes of wheezing, breathlessness, chest tightness and cough, particularly at night and in the early morning. Many cells are involved in the inflammatory response in asthma and, among these, CD4+ Type-2 lymphocytes, mast cells and eosinophils are thought to play a crucial role. In COPD, the poorly reversible airflow limitation is associated with an abnormal inflammatory response of the lungs to noxious particles or gases [2]. This chronic inflammation is characterized by an increased number of CD8+ Type-1 T-lymphocytes and macrophages in the lung tissue and neutrophils in the airway lumen. Lymphocytes, which are markedly different in the two inflammatory conditions, play a crucial role in the pathogenesis of asthma and COPD. In this review, we will discuss the current concepts on the recruitment, homing and activity of lymphocytes in these two respiratory diseases.     

Chemotherapeutic stress mediated by certain antitumor antibiotics induces an atypical CD69+ surface phenotype in peripheral T-lymphocytes.

Surface antigen CD69 is a Type II integral membrane protein that is generally considered a cell activation marker expressed very early in the normal lymphocyte activation cascade. The conformation of this surface antigen suggests a putative role in transmembrane signal transduction, yet the precise function of this surface antigen has not been clearly elucidated. We had previously reported robust atypical CD69 expression in peripheral T-lymphocytes as concentration-dependent, phenotypic responses to actinomycin D-induced chemotherapeutic stress in the absence of secondary stimulation. Additional antitumor antibiotics were evaluated for inductive potential, and the incidence and respective magnitudes of this chemotherapeutic stress-induced shift in lymphocytic CD69 expression were assessed. Results indicated that atypical CD69 expression is a common response to chemotherapy drug-induced stress. Differences in the respective percentages of CD69 + T-lymphocytes, and the resulting numbers of CD69 surface antigens ultimately expressed by these cells, were documented following in vitro drug exposure. The effective drug concentrations required to mediate detectable shifts in the CD69+ phenotype differed among the selected drugs, as well, suggesting a concentration-dependent induction mechanism putatively related to drug modality. Static CD69 expression responses in CD3+ peripheral T-lymphocytes were also documented, which further suggests that the different intracellular modalities do not mediate proportional T-lymphocyte responses through elevated CD69 expression.     

哮喘患者治疗前后气道上皮TSLP表达及炎性因子的相关研究

目的通过对支气管哮喘患者治疗前后TSLP及炎性因子的变化情况的对比研究,分析探讨支气管哮喘的作用机制。方法使用抗炎药物布地奈德对于支气管哮喘患者进行治疗,试验前后对患者TSLP的表达活性、含量及血浆中IL-4,IL-5,IL-13的含量,以及外周血单个核细胞（PBMCs）中CD40、CD80、CD86的表达水平进行检测,采用健康人数据作为对照组,并对检测结果进行统计对比,研究其变化及其之间关系。结果患者经治疗哮喘症状明显减轻,TSLP表达活性以及炎性因子的表达水平都显著减少,与对照组相比更为接近。结论布地奈德等抗炎药物可有效治疗支气管哮喘,降低TSLP等的表达水平,而该类指标与支气管哮喘的加重密切相关。     

Asthma. Eosinophils and neutrophils.

Eosinophils are strongly implicated as a major proinflammatory cell in the pathogenesis of asthma. Basic proteins from the crystalloid granule may be responsible for damage to mucosal epithelium whereas membrane-derived lipid mediators (particularly platelet activating factor and leukotriene C4) might directly influence bronchial smooth muscle contraction, microvascular permeability and mucus hypersecretion. The numbers of eosinophils and their products correlated with the severity of disease whereas successful treatment is usually associated with a resolution of local eosinophilia. Neutrophils may also be implicated in the pathogenesis of asthma but the evidence that this cell per se plays an important role remains controversial. Neutrophil products have the potential for altering airway function. More research is required to define the precise role of this cell type in asthma. It needs to be emphasised that the inflammation associated with bronchial asthma is complex and involves several cell types (i.e. T lymphocytes, mast cells and macrophages) in addition to the eosinophil and neutrophil.     

气道重塑与磷脂酰肌醇3激酶/蛋白激酶B信号通路在支气管哮喘发病机制中的研究进展

支气管哮喘是一种以可逆性气流受限为特征的气道慢性炎症性疾病。在支气管哮喘众多发病机制中,气道重塑与磷脂酰肌醇 3激酶/蛋白激酶B(PI3K/PKB)通路联系紧密。气道重塑与支气管气道平滑肌细胞的增殖和凋亡密切相关。PI3K/PKB信号通路作为细胞内一条重要的信号传导通路,起到抑制细胞凋亡、促进细胞周期的进展,介导细胞增殖等作用,因而可以结合气道重塑与PI3K/PKB通路对支气管哮喘的发病和治疗进行探讨和研究。该研究现对支气管哮喘、气道重塑、PI3K/PKB通路的研究进展进行了综述,以期为支气管哮喘的治疗提供借鉴。     

Asthma. Epithelial cells.

The airway epithelium is the first line of defence against air-borne dusts, vapour, gases and fumes and plays a vital role in the maintenance of physico-chemical homoeostasis. Perturbation of the epithelial cells which predominate within this barrier, may bring about adverse changes in and around the surrounding tissues playing a part in the pathogenesis of asthma. Although the specific mechanism(s) which partake in pathogenesis are not clear, several have been proposed. These include: (1) increased synthesis and release of inflammatory mediators and decreased synthesis of protective mediators; (2) synthesis of inflammatory cytokines; (3) modulation of cell adhesion molecules, important in determination of epithelial architecture; and (4) immunoregulation of the inflammatory cell types. It is likely that these operate together and interact to produce, initially functional changes in the epithelium, which lead eventually to the structural changes that are characteristic of the airway epithelium of asthmatics.     

Effects of saiboku-to on the survival of human eosinophils.

In recent years, bronchial asthma has come to be regarded as a chronic inflammatory disease of the respiratory tract, with mast cells, lymphocytes and eosinophils playing important roles in its pathogenesis. Proteins contained in eosinophil granules, especially major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO), can cause tissue injury. When stimulated, eosinophils release mediators such as leukotriene C4 (LTC4) and platelet activating factors (PAF). Thus, they are recognized as effector cells that are actively involved in the development of allergic inflammation. In this study, eosinophils from healthy volunteers were used to investigate the effects of Saiboku-to on eosinophils whose survival had been prolonged through stimulation with eosinophil-activating cytokines such as interleukin (IL)-3, IL-5 and granulocyte macrophage colony stimulating factors (GM-CSF). As a result, the cytokine-enhanced survival of eosinophils was significantly shortened by the addition of Saiboku-to. These findings suggest that Saiboku-to has the potential to inhibit allergic responses by directly affecting eosinophils which are related to allergic inflammation.     

Modulation of mite antigen-induced immune responses by lecithin-bound iodine in peripheral blood lymphocytes from patients with bronchial asthma.

1. Dermatophagoides farinae (Df) mite antigen induced IgE synthesis associated with an imbalance of cytokine production in mite-sensitive patients with bronchial asthma; increased production of interleukin 4 (IL-4), and decreased production of interferon-gamma (IFN-gamma) was specifically induced in these patients'' lymphocytes. 2. Lecithin-bound iodine (LBI), with which children with bronchial asthma have been successfully treated in the range of 0.5 to 5 microM, concentrations comparable to LBI blood levels in medicated individuals, modified mite antigen-induced immune responses, thereby decreasing abnormal lymphocyte functions. 3. In Df antigen-driven immune responses, inhibition of IgE generation accompanied by suppression of IL-4 and the recovery of IFN-gamma production was successful when LBI was used in vitro. 4. LBI also acted on normal PBMCs by downregulating the IL-4-induced IgE synthesis, phytohaemagglutin (PHA)- and phorbol myristate acetate (PMA) plus calcium ionophore (CaI)-induced IL-4 secretion, and by upregulating purified protein derivatives (PPD)-induced IFN-gamma production. Therefore, LBI was capable of inhibiting the IgE and IL-4 responses and of enhancing IFN-gamma production both from allergen-stimulated atopic cells and from non-atopic cells appropriately stimulated. 5. The expression of human histocompatibility leukocyte antigen (HLA), class II antigens and intercellular adhesion molecule 1 (ICAM-1) on monocytes, crucial molecules for T cell-monocyte interactions, was not altered by LBI. 6. LBI probably acts as an immunomodulator to ameliorate mite antigen-induced abnormal cell-mediated immune responses in patients with bronchial asthma caused by Df antigen thereby leading to improvement of their clinical status.     

Asthma as an inflammatory disease: clinical perspectives.

Asthma is characterised by a persistent, ongoing airway submucosal inflammatory process which may underlie bronchial hyperresponsiveness and airways obstruction. Indirect assessment of airway inflammation includes examination of sputum or serum for eosinophils or eosinophil-derived products, but examination of bronchial mucosal biopsies or bronchoalveolar lavage fluid or cells remains the gold standard. Lymphocyte and eosinophil activation, with the release of certain cytokines such as interleukin-5, lipid mediators such as leukotrienes and eosinophil products such as major basic protein, may be important mechanisms of inflammation in asthma. Less invasive indirect measures of submucosal inflammation are needed to assess the impact of asthma treatment in the clinic. Antiinflammatory treatment in asthma should be introduced as early as possible. A greater understanding of the inflammatory mechanism or of the actions of corticosteroids may lead to the development of more effective and safer drugs for asthma.     

支气管哮喘的炎症免疫调节治疗现状

支气管哮喘是由多种炎性细胞参与,以气道高反应(BAR)为主要病理生理特征的气道慢性特殊性炎症性疾病。其病因与发病机制复杂,气道的变应性炎症是其发病的中心环节,控制气道炎症是针对哮喘病因治疗的主要方法及研究方向。本文就哮喘的免疫学机制和免疫治疗进行概述。     

幽门螺杆菌感染与儿童支气管哮喘患儿循环CD4+CD25+调节性T细胞的相关性分析

目的 探究幽门螺杆菌感染与儿童支气管哮喘患儿循环CD4+CD25+调节性T细胞的相关性.方法 选取本院2015年1月至2016年6月期间收治的支气管哮喘患儿共160例,根据患儿哮喘的发作情况将这160例患儿分为发作组和缓解组,同期选取80例健康儿童作为对照组,检测哮喘儿童的幽门螺杆菌感染情况,比较3组患者CD4+CD25+调节性T细胞的情况.结果 发作组患儿幽门螺杆菌阳性率显著高于缓解组(42.50％比22.50％),差异有统计学意义(x2=12.266,P＜0.05);幽门螺杆菌阴性组患儿CD4+CD25+调节性T细胞水平显著高于阳性组(8.01±2.43)比(5.38±2.16)],差异有统计学意义(F=5.554,P＜0.05).结论 发生幽门螺杆菌感染时,感染加重导致免疫功能异常,使CD4+CD25+调节性T细胞水平降低,从而可能导致了支气管哮喘的发生.     

The pathology of asthma: brief review

The presence of chronic airway inflammation in asthmatic patients has been known for over a century, but the relationship of this inflammatory process to the pathogenesis of reversible airflow obstruction and non-specific bronchial hyperresponsiveness remains unclear. In recent years, the increasing ability to sample the lower respiratory tract of living asthmatic patients, coupled with revolutionary advances in immunology and molecular biology, has resulted in extensive evaluation of inflammatory cells and mediators implicated in the pathogenesis of asthma. In addition, there is increasing recognition that airway remodeling, characterized by thickening of all compartments of the airway wall, may have profound consequences on the mechanics of airway narrowing in asthma and contribute to the chronicity and progression of the disease. In this brief review, I will describe the gross and microscopic pathology of asthma, the process of airway remodeling and its functional consequences, and speculate on future directions to improve our understanding of the structural changes of asthma and their pathogenic role.     

Nerve growth factor and its receptors in asthma and inflammation

Nerve growth factor (NGF) is a high molecular weight peptide that belongs to the neurotrophin family. It is synthesized by various structural and inflammatory cells and activates two types of receptors, the TrkA (tropomyosin-receptor kinase A) receptor and the p75^NTR receptor, in the death receptor family. NGF was first studied for its essential role in neuronal growth and survival. Recent reports indicate that it may also help mediate inflammation, especially in the airways. Several studies in animals have reported that NGF may induce bronchial hyperresponsiveness, an important feature of asthma, by increasing sensory innervation. It may also induce migration and activation of inflammatory cells, which infiltrate the bronchial mucosa, and of structural cells, including epithelial, smooth muscle cells and pulmonary fibroblasts. Increased NGF expression and release is observed in asthma patients after bronchial provocation with allergen. Taken together, the data from the literature suggest that NGF may play a role in inflammation, bronchial hyperresponsiveness and airway remodelling in asthma and may help us to understand the neuro-immune cross-talk involved in chronic inflammatory airway diseases.     

Signal transduction of IL-13 and its role in the pathogenesis of bronchial asthma

Interleukin-13 (IL-13) is a Th2-type cytokine, secreted from CD4(+) T cells, mast cells, basophils and eosinophils. The human IL-13 gene locates at 5q31, generating a cluster with other Th2-type cytokines such as IL-4 and IL-5. Although the homology between IL-13 and IL-4 at the amino acid level is only about 25%, the IL-13 structure determined by NMR is very similar to that of IL-4. Both cytokines share their receptors and signal pathways, giving these two cytokines similar biological properties. However, the important role of IL-13 in the pathogenesis of bronchial asthma has recently been recognized, based mainly on analyses of mouse models. IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic reagent for bronchial asthma. In this article, we summarize the signal transduction pathway of IL-13, the pathological roles of IL-13 in bronchial asthma and the reagents to inhibit IL-13 signals that are now under development.     

Effect of topical immunomodulators on acute allergic inflammation and bronchial hyperresponsiveness in sensitised rats

We examined the effects of different immunomodulators administered topically on asthmatic responses in a rat model of asthma. Sensitised Brown-Norway rats were administered rapamycin, SAR943 (32-deoxorapamycin), IMM125 (a hydroxyethyl derivative of D-serine(8)-cyclosporine), and budesonide by intratracheal instillation 1 h prior to allergen challenge. Allergen exposure induced bronchial hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid, and also an increase in eosinophils and CD2+, CD4+ and CD8+ T cells in the airways. Interleukin-2, interleukin-4, interleukin-5, interleukin-10, and interferon-gamma mRNA expression was upregulated by allergen exposure. Budesonide abolished airway inflammation, suppressed the mRNA expression for interleukin-2, interleukin-4, and interleukin-5 (P<0.03), and bronchial hyperresponsiveness (P<0.05). IMM125 suppressed airway infiltration of eosinophils, and CD8+ T cells (P<0.02), and prevented the upregulated mRNA expression for interleukin-4, interleukin-5, and interferon-gamma (P<0.02). Rapamycin suppressed CD8+ T cell infiltration in airway submucosa (P<0.03), and mRNA expression for interleukin-2 (p<0.002), while SAR943 suppressed interleukin-2, interleukin-4, and interferon-gamma mRNA (P<0.05). IMM125, rapamycin and SAR943 did not alter airway submucosal CD2+ and CD4+ T cell infiltration, and bronchial hyperresponsiveness. CD8+ T cells, in contrast to CD4+ T cells, are more susceptible to the inhibition by IMM125 and rapamycin, which also caused greater suppression of Th1 compared to Th2 cytokine mRNA expression. In this acute model of allergic inflammation, differential modulation of Th1 and Th2 cytokines may determine the effects of various immunomodulators on airway inflammation and bronchial hyperresponsiveness.