Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result ...of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as “Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children).” Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment.
Epithelium dysfunction in asthma Holgate, Stephen T., MD, DSc
Journal of allergy and clinical immunology,
12/2007, Letnik:
120, Številka:
6
Journal Article
Recenzirano
Although asthma is an inflammatory disorder of the conducting airways involving TH 2-type T cells, there is increasing evidence for an important role played by the epithelium in orchestrating the ...inflammatory response by interacting with multiple environmental factors to produce a chronic wound scenario involving tissue injury and aberrant repair. Part of this abnormal response is the consequence of impaired barrier function caused by a primary disruption of epithelial tight junctions that allows inhaled substances to pass more easily into the airway wall to interact with immune and inflammatory cells. Aberrant communication between the damaged and stressed epithelium leads to the generation of growth factors that interact with the underlying mesenchyme to promote airway remodeling responses and a more chronic and persistent inflammatory phenotype. Disordered epithelial function with reduced antioxidant defense and impaired capacity to produce primary IFNs may also account for asthmatic susceptibility to air pollution and respiratory virus infection, respectively. Considering asthma as a disease of impaired barrier function opens new opportunities for therapeutic intervention or prevention by agents that could increase the airways resistance to the inhaled environment rather than suppressing the immune or inflammatory response.
Defective epithelial barrier function in asthma Xiao, Chang, PhD; Puddicombe, Sarah M., PhD; Field, Sarah, PhD ...
Journal of allergy and clinical immunology,
09/2011, Letnik:
128, Številka:
3
Journal Article
Recenzirano
Background Asthma is a complex disease involving gene and environment interactions. Although atopy is a strong predisposing risk factor for asthma, local tissue susceptibilities are required for ...disease expression. The bronchial epithelium forms the interface with the external environment and is pivotally involved in controlling tissue homeostasis through provision of a physical barrier controlled by tight junction (TJ) complexes. Objectives To explain the link between environment exposures and airway vulnerability, we hypothesized that epithelial TJs are abnormal in asthma, leading to increased susceptibility to environmental agents. Methods Localization of TJs in bronchial biopsies and differentiated epithelial cultures was assessed by electron microscopy or immunostaining. Baseline permeability and the effect of cigarette smoke and growth factor were assessed by measurement of transepithelial electrical resistance and passage of fluorescently labeled dextrans. Results By using immunostaining, we found that bronchial biopsies from asthmatic subjects displayed patchy disruption of TJs. In differentiated bronchial epithelial cultures, TJ formation and transepithelial electrical resistance were significantly lower ( P < .05) in cultures from asthmatic donors (n = 43) than from normal controls (n = 40) and inversely correlated with macromolecular permeability. Cultures from asthmatic donors were also more sensitive to disruption by cigarette smoke extract. Epidermal growth factor enhanced basal TJ formation in cultures from asthmatic subjects ( P < .01) and protected against cigarette smoke–induced barrier disruption ( P < .01). Conclusions Our results show that the bronchial epithelial barrier in asthma is compromised. This defect may facilitate the passage of allergens and other agents into the airway tissue, leading to immune activation and may thus contribute to the end organ expression of asthma.
BACKGROUND High bronchodilator reversibility in adult asthma is associated with distinct clinical characteristics. This analysis compares lung function, biomarker profiles, and disease control in ...patients with high reversibility (HR) and low reversibility (LR) asthma. METHODS A retrospective analysis was performed with data from two completed clinical trials of similar design. Patients were divided into HR and LR subgroups based on their response to bronchodilators (HR = ⋄FEV1 postbronchodilator > 20%). Blood eosinophil count, serum IgE level, and fraction of exhaled nitric oxide concentration, biomarkers commonly used to stratify patients into T-helper (Th)-2-high vs Th2-low phenotypes, were measured in patients with not well controlled (1.5 ≤ Asthma Control Questionnaire ACQ ≤ 2.143) and very poorly controlled (ACQ > 2.143) disease. RESULTS The majority of patients in the HR and LR subgroups displayed Th2-low biomarker profiles and very poor disease control. HR was more frequently associated with Th2-high biomarker profiles (40.1% vs 29.4%, P = .006), lower lung function (FEV1 , 63.5 ± 7.7% predicted vs 67.9 ± 8.4% predicted; P .001), and atopy (93.7% vs 86.5%, P = .005). CONCLUSIONS HR is a physiologic indicator of reduced lung function and is more often associated with elevations in Th2 biomarkers than LR in moderate to severe asthma. However, the majority of patients with HR and LR asthma in this analysis had a Th2-low biomarker profile. Moreover, a Th2-high biomarker profile was not associated with worse disease control.
Genetics of allergic disease Holloway, John W., PhD; Yang, Ian A., MBBS, PhD; Holgate, Stephen T., MD, DSc, FMed Sci
Journal of allergy and clinical immunology,
02/2010, Letnik:
125, Številka:
2
Journal Article
Recenzirano
Allergic diseases are complex genetic diseases resulting from the effect of multiple genetic and interacting environmental factors on their pathophysiology. Recent years have seen considerable ...progress in unraveling the contribution of these factors to an individual subject's susceptibility to, subsequent development of, and severity of disease. This has resulted in increasing insight into novel areas of allergic disease pathophysiology, for example the significant role played by locally acting tissue susceptibility factors like epithelial/epidermal barrier function and remodeling, such as filaggrin, ADAM33 , and GSDML / ORMDL3 , in patients with atopic dermatitis and asthma. Furthermore, studies of gene-environment interactions and Mendelian randomization approaches have led to increased insight into the importance of environmental triggers for allergic disease. Studies of the timing of action of genetic variants in determining disease susceptibility have highlighted the importance of in utero development and early life in determining susceptibility to allergic disease. In the future, genetic discoveries in allergic disease will potentially lead to better endophenotyping, prognostication, prediction of treatment response, and insights into molecular pathways to develop more targeted therapy for these conditions.
Background Because TNF-α is increased in severe asthma, we hypothesized that TNF-α contributes to barrier dysfunction and cell activation in bronchial epithelial cells. We further hypothesized that ...src-family kinase inhibition would improve barrier function in healthy cells in the presence of TNF-α and directly in cultures of severe asthmatic cells where the barrier is disrupted. Objectives We assessed the effect of TNF-α, with or without src-family kinase inhibitor SU6656, on barrier properties and cytokine release in differentiated human bronchial epithelial cultures. Further, we tested the effect of SU6656 on differentiated primary cultures from severe asthma. Methods Barrier properties of differentiated human bronchial epithelial air-liquid interface cultures from healthy subjects and subjects with severe asthma were assessed with transepithelial electrical resistance and fluorescent dextran passage. Proteins were detected by immunostaining or Western blot analysis and cytokines by immunoassay. Mechanisms were investigated with src kinase and other inhibitors. Results TNF-α lowered transepithelial electrical resistance and increased fluorescent dextran permeability, caused loss of occludin and claudins from tight junctions with redistribution of p120 catenin and E-cadherin from adherens junctions, and also increased endogenous TNF-α, IL-6, IL-1β, IL-8, thymic stromal lymphoprotein, and pro–matrix metalloprotease 9 release. SU6656 reduced TNF-α–mediated paracellular permeability changes, restored occludin, p120, and E-cadherin and lowered autocrine TNF-α release. Importantly, SU6656 improved the barrier properties of severe asthmatic air-liquid interface cultures. Redistribution of E-cadherin and p120 was observed in bronchial biopsies from severe asthmatic airways. Conclusions Inhibiting TNF-α or src kinases may be a therapeutic option to normalize barrier integrity and cytokine release in airway diseases associated with barrier dysfunction.
Background A disintegrin and metalloprotease 33 (ADAM33) polymorphism is strongly associated with asthma and bronchial hyperresponsiveness. Although considered to be a mesenchymal cell–specific gene, ...recent reports have suggested epithelial expression of ADAM33 in patients with severe asthma. Objectives Because dysregulated expression of ADAM33 can contribute to disease pathogenesis, we characterized the mechanism or mechanisms that control its transcription and investigated ADAM33 expression in bronchial biopsy specimens and brushings from healthy and asthmatic subjects. Methods The ADAM33 promoter and CpG island methylation were analyzed by using bioinformatics, luciferase reporters, and bisulfite sequencing of genomic DNA. Epithelial-mesenchymal transition was induced by using TGF-β1. ADAM33 mRNA was scrutinized in bronchial biopsy specimens and brushings by using reverse transcriptase–quantitative polymerase chain reaction, melt-curve analysis, and direct sequencing. Results The predicted ADAM33 promoter (−550 to +87) had promoter transcriptional activity. Bisulfite sequencing showed that the predicted promoter CpG island (−362 to +80) was hypermethylated in epithelial cells but hypomethylated in ADAM33-expressing fibroblasts. Treatment of epithelial cells with 5-aza-deoxycytidine caused demethylation of the CpG island and induced ADAM33 expression. In contrast, phenotypic transformation of epithelial cells through a TGF-β–induced epithelial-mesenchymal transition was insufficient to induce ADAM33 expression. ADAM33 mRNA was confirmed in bronchial biopsy specimens, but no validated signal was detected in bronchial brushings from healthy or asthmatic subjects. Conclusion The ADAM33 gene contains a regulatory CpG island within its promoter, the methylation status of which tightly controls its expression in a cell type–specific manner. ADAM33 repression is a stable feature of airway epithelial cells, irrespective of disease.
Using genetics to predict the natural history of asthma? Holloway, John W., PhD; Arshad, Syed H., MD, FRCP; Holgate, Stephen T., MD, DSc, FMed Sci
Journal of allergy and clinical immunology,
08/2010, Letnik:
126, Številka:
2
Journal Article
Recenzirano
Clinical practice reminds us that there is considerable variability in the course of asthma over time. Treatment of patients with asthma would be considerably improved if one could accurately predict ...the likely course of disease over the life course. Recently, with the advent of the era of genome-wide association studies, there has been a monumental shift in our understanding of the genetic factors that underlie inherited susceptibility to asthma. Genes have been identified that modulate many aspects of the natural history of asthma, such as susceptibility to atopy, altered lung development, and susceptibility to more severe disease. Heritability studies have even suggested a role for genetic factors in remission of asthma. However, although the discovery of novel genetic factors underlying disease susceptibility has undoubtedly improved our understanding of disease pathogenesis, whether these advances have improved the ability to predict the natural history in individual patients is questionable, and the application of genetic testing to clinical practice remains some way off.
Background Several studies have suggested that chromosome 19q13.1-3 contains asthma susceptibility genes. Objective Linkage and association analyses using 587 United Kingdom and Dutch asthma families ...(n = 2819 subjects) were used to investigate this region. Methods A 3-phase procedure was used: (1) linkage and association analyses using 15 microsatellite markers spanning 14.4 mega base pairs (Mbps) on 19q13, (2) fine mapping of the refined region using 26 haplotype tagging single nucleotide polymorphisms (SNPs), and (3) dense gene analyses using 18 SNPs evaluated for association with asthma, bronchial hyperresponsiveness (BHR), FEV1 , plasma urokinase plasminogen activator receptor (PLAUR), and rate of annual FEV1 decline in subjects with asthma. Results The microsatellite analyses provided tentative support for an asthma/lung function susceptibility locus (48.9-49.1Mbps), and fine mapping localized modest association to the PLAUR gene. PLAUR SNPs in the 5′ region, intron 3, and 3′ region are associated with asthma and BHR susceptibility and predict FEV1 and plasma PLAUR levels. SNPs in the 5′ region showed association for asthma (2 populations), FEV1 (2 populations), and BHR (2 populations) phenotypes. SNPs in intron 3 showed association with asthma (2 populations) and BHR (3 populations). Importantly, the same 5′ region and intron 3 SNPs were associated with plasma PLAUR levels. The same 5′ region and 3′ region SNPs were found to be determinants of FEV1 decline in subjects with asthma. Conclusion This study represents the first report to identify PLAUR as a potential asthma susceptibility gene and determine PLAUR regions underlying this association, including a role in influencing plasma PLAUR levels. Finally, the association of PLAUR with lung function decline supports a role for PLAUR in airway remodeling in asthma.
Background Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification. ...Objective We sought to identify asthma susceptibility genes in children. Methods A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n = 116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n = 112) and normal controls (n = 165). A genomic region containing the ATPAF1 gene was found to be significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in 8 independent study populations of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in 2 consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatic patients and controls. Results Asthma was found to be associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene, with 2 SNPs achieving significance at a genome-wide level ( P = 2.26 × 10−5 to 2.2 × 10−8 ). Asthma severity was also found to be associated with SNPs and SNP haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the 4 non-Hispanic populations. Haplotype associations were also confirmed in the non-Hispanic populations ( P = .045-.0009). ATPAF1 total RNA expression was significantly ( P < .01) higher in bronchial biopsies from asthmatic patients than from controls. Conclusion Genetic variation in the ATPAF1 gene predisposes children of different ancestries to asthma.
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