Therapeutic Response to Asthma Medications

Asthma is a major social and economic burden. Studies have shown that genetic polymorphisms can influence drug efficacy and/or toxicity. The understanding of the pharmacogenetics of asthma will allow therapeutic regimens to be tailored on an individual basis. It is hoped that linkage and association studies will define new therapeutic targets for asthma but until then, studies have focused on improving response to beta(2)-adrenoceptor agonist and leukotriene modifier therapy. Genetic polymorphism may account for interindividual differences in toxicity and efficacy of asthma medications. To date, single nucleotide polymorphism and limited haplotype analysis have provided inconclusive evidence as to how genotype predictors can be used to optimize current asthma therapies based on each patient's genetic profile.     

Asthma and chronic obstructive pulmonary disease: common genes, common environments?

Asthma and chronic obstructive pulmonary disease (COPD) show similarities and substantial differences. The Dutch hypothesis stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the timing and type of environmental exposures (Postma and Boezen, Chest 2004;126:96S-104S). Thus, a particular group of shared genetic factors may lead to asthma when combined with specific environmental factors that are met at a certain stage in life, whereas combination with other environmental factors, or similar environmental factors at a different stage in life, will lead toward COPD. Multiple genes have been found for asthma and COPD. In addition to genes unique to these diseases, some shared genetic risk factors exist. Moreover, there are both common host risk factors and environmental risk factors for asthma and COPD. Here we put forward, based on the data available, that genes that affect lung development in utero and lung growth in early childhood in interaction with environmental detrimental stimuli, such as smoking and air pollution, are contributing to asthma in childhood and the ultimate development of COPD. Additional genes and environmental factors then drive specific immunological mechanisms underlying asthma, and others may contribute to the ultimate development of specific subtypes of COPD (i.e., airway disease with mucous hypersecretion, small airway disease, and emphysema). The genetic predisposition to the derailment of certain pathways may further help to define subgroups of asthma and COPD. In the end this may lead to stratification of patients by their genetic make-up and open new therapeutic prospects.     

支气管哮喘与Toll-样受体的关系研究进展

支气管哮喘(简称哮喘)是由多种细胞(如嗜酸粒细胞、肥大细胞、淋巴细胞、中性粒细胞、气道上皮细胞等)和细胞组分参与的气道慢性炎症性疾病,是遗传易感个体与各种环境因素共同作用的结果.研究发现,Toll-样受体(TLR)和免疫细胞在哮喘的发生发展中起着重要作用.TLR通过识别多种病原体,激活Th1或Th2等免疫反应,被认为是防止或促进哮喘发生一个的重要因素.本文对TLR及其相关配体在哮喘发病机制中的作用作以下综述,为哮喘的治疗提供新思路.     

Biologic therapy in asthma: entering the new age of personalized medicine

Objective: Asthma is a common chronic disease with various phenotypes and therapeutic responses. Unlike other diseases, current anti-inflammatory treatment with corticosteroids does not include any reference to biological measures which may vary among different asthma phenotypes. Morbidity from uncontrolled asthma suggests a need for specific targeted treatment approaches such as biologic medications. In half of asthmatics, chronic airway inflammation may be driven by T helper (Th)-2 cells, which release pro-inflammatory cytokines, such as interleukin (IL)-4, IL-5 and IL-13, contributing to eosinophil inflammation and IgE production. Earlier studies of cytokine-targeted biologic therapy on non-phenotyped asthma patients were generally not clinically effective. Methods: Literature published from 1958–2013 was identified through PubMed using the search terms which included asthma and therapy. A total of 32 studies were reviewed covering both pediatric and adult asthmatics and included double-blind randomized placebo-controlled trials testing efficacy of biologic agents to treat asthma. Results: More recent approaches to personalized medicine with expression profiling studies, genetic analysis and clinical biomarkers of Th2 inflammation have allowed identification of asthma phenotypes including a Th2 “high” phenotype. Studies targeting IgE, IL-5, IL-13 and the IL4 receptor alpha chain have shown some efficacy in phenotyped patients. For those without evidence of Th2 inflammation, no specific therapies have been identified. Conclusions: In recent years, the identification of Type-2 cytokine “high” asthma in numerous studies has predicted the clinical response to the Th2 associated therapies. It is not yet clear whether all Type 2 high asthma will respond similarly to IL-4, 5 and 13 approaches.     

The importance of genetic influences in asthma.

Asthma is a complex genetic disorder in which the mode of inheritance is not known. Many segregation studies suggest that a major gene could be involved in asthma, but until now different genetic models have been obtained. Twin studies, too, have shown evidence for genetic influences in asthma, but have also revealed substantial evidence for environmental influences, in which nonshared environmental influences appeared to be important. Linkage, association studies and genome-wide screening suggest that multiple genes are involved in the pathogenesis of asthma. At least four regions of the human genome, chromosomes 5q31-33, 6p21.3, 11q13 and 12q14.3-24.1, contain genes consistently found to be associated with asthma and associated phenotypes. Not only genes associated with asthma but also genes which are involved in the development and outcome of asthma will be found in the future. This will probably provide greater insight into the identification of individuals at risk of asthma and early prevention and greater understanding for guiding therapeutic intervention in asthma. Exchange of information between researchers involved in the genetics of asthma is important because of mandatory agreement on phenotypes and analytical approaches. Genetics will contribute to the a better understanding and management of asthma in the future.     

ADAM33: a newly identified protease involved in airway remodelling

Asthma is a complex disorder in which major genetic and environmental factors interact to both initiate the disease and modify its progression. While asthma is recognised as a disorder of the conducting airways characterised by Th2-directed inflammation, it is being increasingly apparent that alteration of the structural cells of the airways (airway remodelling) is also fundamental to disease chronicity and severity. The gene ADAM33, encoding a novel member of a identified as an asthma susceptibility gene as the result of a positional cloning effort in a cohort of families recruited form the UK and USA. Subsequent genetic studies have now provided evidence that ADAM33 may be involved in determining lung function throughout life, associated with early life lung function as well as increased decline therapeutic intervention in asthma and future work will focus on the mechanisms by which it alters lung function and bronchial hyperresponsiveness.     

Evolution and respiratory genetics.

Evolution is a plausible explanation for between-population differences in particular allele frequencies if: the genes involved have related functions; the heterogeneous alleles involved have similar functional consequences; the involved genes are not linked chromosomally; and the patterns observed would result in a biologically plausible, survival-enhancing gene-environment interaction. However, possible evolutionary effects have to be differentiated from founder effects and random genetic drift. The current authors have noted the existence of a consistent pattern of allelic frequencies in genes related to T-helper 2 (Th2) immune responses in humans of different ancestral backgrounds, residing in climatically similar regions. Th2 responses are thought to have evolved in mammals to resist infection by parasites, particularly helminths. Modern man arose in tropical Africa where helminths thrived. Relatively recently, humans migrated to cooler or drier climates where most helminths struggled to reproduce. The genetic tendency to strong Th2 responses may have become a health liability, the reduction in risk from parasites being counterbalanced by an increased inherited propensity to atopic or allergic diseases. The pattern noted by the present authors includes specific alleles of interleukin-4 and its receptor, interleukin-13, interleukin-10, the beta chain of the high-affinity receptor for immunoglobulin E, the beta(1)-adrenergic receptor, and the alpha chain of tumour necrosis factor. These population-specific polymorphism profiles are likely to be relevant in current disease patterns. The high incidence of asthma in migrants from tropical locations to affluent temperate countries is likely to be related to these patterns. Of even more concern is the possibility that increasing westernisation among the approximately 2 billion people living in the tropics will produce rapidly increasing levels of asthma, as these populations have a high genetic predisposition to allergic disease.     

New immunological approaches and cytokine targets in asthma and allergy.

The aims of current asthma treatment are to suppress airway inflammation and control symptoms, and corticosteroids maintain a commanding position in this role. Steroids effectively suppress inflammation in the majority of patients but have little impact on the natural history of this disease. In severe asthmatics, corticosteroids may have relatively less beneficial effects. Recent advances in understanding the inflammatory and immunological mechanisms of asthma have indicated many potential therapeutic avenues that may prevent or reverse abnormalities that underlie asthma. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which may provide valuable flexibility in the therapeutic approach to asthma. The novel immunological approaches include the prevention of T-cell activation, attempts to influence the balance of T-helper cell (Th) populations to inhibit or prevent Th2-derived cytokine expression, and the inhibition or blockade of the downstream actions of these cytokines such as effects on immunoglobulin-E and eosinophils. These approaches provide broad as well as highly specific targeting, and also prospects for prevention and reversal of immunological and inflammatory abnormalities associated with asthma. Hopefully, the development of effective antiasthma agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of asthma.     

Notch通路与支气管哮喘相关的研究进展

近年来大量研究表明Notch通路在支气管哮喘(哮喘)的发生、发展中有十分重要的作用。Notch通路调控肺组织的发生发育,可以决定细胞的分化方向、调控肺泡和肺血管的发育;Notch通路参与T细胞调节,通过改变Th1/Th2平衡,影响Th17、Treg、树突状细胞表达等途径,导致哮喘的发生、发展;Notch通路也通过改变各...     

Invariant natural killer T (iNKT) cells in asthma: a novel insight into the pathogenesis of asthma and the therapeutic implication of glycolipid ligands for allergic diseases.

Allergic bronchial asthma is a complex inflammatory diseases originated from dysregulated immune responses in the respiratory mucosa. The inflammatory state in asthmatic lung is characterized by massive infiltration with eosinophils, lymphocytes, and mast cells in the airway mucosa leading to airway hyperseisitivity, goblet cell hyperplasia and mucus overproduction. The inflammatory process is thought to be the result of intensive T helper (Th) 2-biased immune response. Over the past several years, there has been enormous progress in understanding the mechanisms for development of Th2-biased responses after inhaled exposure to allergens and the characteristics of CD4+ T cells prominently involved in this process. Recently, a new population of T cells, invariant natural killer T (iNKT) cells has been shown to play an important role in the pathogenesis of mouse model of allergic airway inflammation. iNKT cells are one of the most potent immune modulators through a massive production of a various cytokines including IL-4 and IFN-gamma upon activation, and are involved in a variety of immunoregulations including infection, autoimmunity, and tumor surveillance. The potent pathogenic role of iNKT cells in the development of bronchial asthma is due to their ability to produce predominant Th2 cytokines in a given condition. The involvement of iNKT cells in the pathogenesis of asthma might have been underestimated in the past studies demonstrating the involvement of CD4+ T cells in asthma because of the difficulty in the detection of iNKT cells. Meanwhile, growing evidences have demonstrated that iNKT cells could be a promising target for immune-based therapies for autoimmune diseases, tumor, and infection due to the invariance of their TCR usage, the restriction to the evolutionally-conserved non-polymorphic antigen-presenting molecule CD1d, and their outstanding ability to produce both Th1- and Th2-cytokines. In this review, we will overview current understanding of the pathophysiological roles of iNKT cells in asthma. We would also discuss on possible therapeutic approaches to bronchial asthma employing glycolipid ligands for iNKT cells.     

Maternal influence in the transmission of asthma susceptibility

Asthma is one of the most common chronic diseases in children, with increasing morbidity and mortality. A genetic predisposition and exposure to allergens have been implicated as major risk factors for the development of asthma. However, increasing evidence indicates that the mother plays a crucial role in mediating the development of fetal-infant immune responses to inhaled allergens. The exact nature and mechanism of this maternal influence and how it might be associated with the development of allergic sensitization and asthma are not clear. Under normal conditions, the maternal environment during pregnancy promotes an initial Th2 skewed immune response in the offspring which transitions to a nonallergic Th1 type response after birth. However, the allergic mother's influence may delay the normal transition to a nonallergic immune response to inhaled allergens in her children, thus increasing the risk for the development of allergic sensitization and/or asthma. Understanding the underlying mechanisms by which the maternal immune environment can influence the development of the fetal-infant immune response to inhaled allergens may lead to identifying new targets for the prevention of allergic sensitization and asthma.     

Immunopathologie de l'asthme sévère

Severe asthma represents a heterogeneous entity for which the immunopathology is poorly understood, in part because of the difficulty of obtaining material in situ material from patients. There are two types of severe asthma, depending on the presence or absence of eosinophils. The pathophysiology of severe asthma of early onset with eosinophilia is similar to that of less severe asthma, with infiltration of Th2 lymphocytes; such cases are more likely to have exacerbations. When the onset occurs later, asthma is much more like the hypereosinophilic syndromes. Severe asthma without eosinophilia is more often accompanied by neutrophil infiltration; this type of asthma responds poorly to corticoids. Induced sputum can be used for non-invasive longitudinal follow-up of bronchial inflammation in severe asthma, allowing evaluation of cellular activation during and between exacerbations. The ISEA study (Induced Sputum in Exacerbations of Asthma) revealed that simultaneous activation of Th1 and Th2 lymphocytes and a greater deficiency of T regulatory lymphocytes occur during the course of exacerbations. This type of approach is indispensable for the identification of relevant therapeutic targets, and ultimately for the identification of early markers that are predictive of exacerbations.     

IL-13:一个前景广阔的治疗支气管哮喘的靶位点

支气管哮喘(简称哮喘)是最常见的过敏性疾病,它是多种细胞参与的慢性气道炎症.大量的实验研究已证实,白介素13(interleukin-13,IL-13)在哮喘发病机制中起中轴作用.也有研究表明,编码IL-13的信号分子的几个基因的遗传联合在哮喘患者体内有很高的表达.因此,众多哮喘的治疗因子中,IL-13及其信号途径作为有前景的治疗靶位点终将展示其诱人的临床价值,为哮喘治疗提供新思路.那么应用IL-13的对抗物阻断IL-13的生物活性对于改善治疗哮喘应该是一个好策略.     

IL-13:一个前景广阔的治疗支气管哮喘的靶位点

支气管哮喘(简称哮喘)是最常见的过敏性疾病,它是多种细胞参与的慢性气道炎症.大量的实验研究已证实,白介素13(interleukin-13,IL-13)在哮喘发病机制中起中轴作用.也有研究表明,编码IL-13的信号分子的几个基因的遗传联合在哮喘患者体内有很高的表达.因此,众多哮喘的治疗因子中,IL-13及其信号途径作为有前景的治疗靶位点终将展示其诱人的临床价值,为哮喘治疗提供新思路.那么应用IL-13的对抗物阻断IL-13的生物活性对于改善治疗哮喘应该是一个好策略.     

IL-13:一个前景广阔的治疗支气管哮喘的靶位点

支气管哮喘(简称哮喘)是最常见的过敏性疾病,它是多种细胞参与的慢性气道炎症.大量的实验研究已证实,白介素13(interleukin-13,IL-13)在哮喘发病机制中起中轴作用.也有研究表明,编码IL-13的信号分子的几个基因的遗传联合在哮喘患者体内有很高的表达.因此,众多哮喘的治疗因子中,IL-13及其信号途径作为有前景的治疗靶位点终将展示其诱人的临床价值,为哮喘治疗提供新思路.那么应用IL-13的对抗物阻断IL-13的生物活性对于改善治疗哮喘应该是一个好策略.     

IL-13:一个前景广阔的治疗支气管哮喘的靶位点

支气管哮喘(简称哮喘)是最常见的过敏性疾病,它是多种细胞参与的慢性气道炎症.大量的实验研究已证实,白介素13(interleukin-13,IL-13)在哮喘发病机制中起中轴作用.也有研究表明,编码IL-13的信号分子的几个基因的遗传联合在哮喘患者体内有很高的表达.因此,众多哮喘的治疗因子中,IL-13及其信号途径作为有前景的治疗靶位点终将展示其诱人的临床价值,为哮喘治疗提供新思路.那么应用IL-13的对抗物阻断IL-13的生物活性对于改善治疗哮喘应该是一个好策略.     

IL-13:一个前景广阔的治疗支气管哮喘的靶位点

支气管哮喘(简称哮喘)是最常见的过敏性疾病,它是多种细胞参与的慢性气道炎症.大量的实验研究已证实,白介素13(interleukin-13,IL-13)在哮喘发病机制中起中轴作用.也有研究表明,编码IL-13的信号分子的几个基因的遗传联合在哮喘患者体内有很高的表达.因此,众多哮喘的治疗因子中,IL-13及其信号途径作为有前景的治疗靶位点终将展示其诱人的临床价值,为哮喘治疗提供新思路.那么应用IL-13的对抗物阻断IL-13的生物活性对于改善治疗哮喘应该是一个好策略.     

IL-13:一个前景广阔的治疗支气管哮喘的靶位点

支气管哮喘(简称哮喘)是最常见的过敏性疾病,它是多种细胞参与的慢性气道炎症.大量的实验研究已证实,白介素13(interleukin-13,IL-13)在哮喘发病机制中起中轴作用.也有研究表明,编码IL-13的信号分子的几个基因的遗传联合在哮喘患者体内有很高的表达.因此,众多哮喘的治疗因子中,IL-13及其信号途径作为有前景的治疗靶位点终将展示其诱人的临床价值,为哮喘治疗提供新思路.那么应用IL-13的对抗物阻断IL-13的生物活性对于改善治疗哮喘应该是一个好策略.     

IL-13:一个前景广阔的治疗支气管哮喘的靶位点

支气管哮喘(简称哮喘)是最常见的过敏性疾病,它是多种细胞参与的慢性气道炎症.大量的实验研究已证实,白介素13(interleukin-13,IL-13)在哮喘发病机制中起中轴作用.也有研究表明,编码IL-13的信号分子的几个基因的遗传联合在哮喘患者体内有很高的表达.因此,众多哮喘的治疗因子中,IL-13及其信号途径作为有前景的治疗靶位点终将展示其诱人的临床价值,为哮喘治疗提供新思路.那么应用IL-13的对抗物阻断IL-13的生物活性对于改善治疗哮喘应该是一个好策略.     

IL-13:一个前景广阔的治疗支气管哮喘的靶位点

支气管哮喘(简称哮喘)是最常见的过敏性疾病,它是多种细胞参与的慢性气道炎症.大量的实验研究已证实,白介素13(interleukin-13,IL-13)在哮喘发病机制中起中轴作用.也有研究表明,编码IL-13的信号分子的几个基因的遗传联合在哮喘患者体内有很高的表达.因此,众多哮喘的治疗因子中,IL-13及其信号途径作为有前景的治疗靶位点终将展示其诱人的临床价值,为哮喘治疗提供新思路.那么应用IL-13的对抗物阻断IL-13的生物活性对于改善治疗哮喘应该是一个好策略.