Pathogenesis Of Severe Asthma Research Articles

The Editor takes a closer look at some of this month's articles

Clinical & Experimental AllergyVolume 43, Issue 9 p. 977-977 Editor's ChoiceFree Access The Editor takes a closer look at some of this month's articles First published: 20 August 2013 https://doi.org/10.1111/cea.12174AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat T cells and asthma: complexity rather than duality The Th2 paradigm of asthma has gained considerable traction based largely on the allergen challenge model of asthma in mice which is a Th2 dominant. The mutual inhibition of Th1 and Th2 subsets led to a persuasive if in retrospect over-simplistic view of asthma as Th2 disease, where Th1 immune responses were suppressed. However, a more sophisticated awareness of the degree of heterogeneity in asthma together with the proliferation in the number of T cells subsets, their plasticity and complexity of interaction demands a re-evaluation of this concept 1. Seys et al. (pp. 1009-1017) contribute to this debate by demonstrating complex patterns of T cell associated cytokines in asthma based on measurement of sputum mRNA. Strikingly, they found in some subjects combined Th2 and Th17 related cytokines and this was associated with more severe disease. Studies such as this linking patterns of T cell activation with clinical phenotypes will allow us to describe endotypes of asthma with greater confidence 2. Sven Seys Radar plot representing the proportion of patients (%) with increased sputum mRNA of a particular cytokine [see Figure 1 in S. F. Seys et al. (pp. 1009-1017)]. T cells and asthma: how important are Th17 cells? Continuing the theme of T cells and asthma a subset that is gaining increasing attention in asthma are Th17 cells that release the cytokines IL-17A and IL-17F 3. Tsai et al. (pp. 1018-1026) have investigated expression of Th17 cells in childhood asthma of varying severity by measuring the number of Th17 cells in peripheral blood and serum IL-17 concentrations. They related this to production of exhaled nitric oxide (eNO) and severity of disease. They found an increased concentration of IL-17 in the serum in asthma as well as an increased percentage of Th17 cells, particularly in those with more severe disease. This correlated with eNO. This study provides further support for the idea that Th17 mediated inflammation is important in asthma. Dr. Jien-Wen Chien Associations between serum IL-17 and fractional exhaled nitric oxide [see Figure 2 in J.-W. Chien et al. (pp. 1018-1026)]. Nasal polyps: interaction between infection and vascular proliferation Nasal polyposis is a common and very unpleasant condition, the cause of which remains obscure. Nasal polyps are part of a group of conditions that cause chronic rhino sinusitis, and there is considerable interest in the interplay between sinus infection and the chronic inflammation, including the increased vascularity, that characterizes nasal polyps. Cho et al. (pp. 1038-1047) have studied this relationship in vitro by investigating the interaction between LPS and vascular endothelial growth factor (VEGF) production in nasal polyp fibroblasts. They show that LPS dramatically induced VEGF production via a TLR4-Akt-dependent pathway, providing evidence that bacterial infection can mediate the dramatic remodelling of the nasal mucosa seen in this disease. Professor Heun-Man Lee VEGF protein expression level was examined by immunofluorescence staining. [see Figure 3 in J.-S. Cho et al. (pp.1038-1047)]. References 1Poon AH, Eidelman DH, Martin JG, Laprise C, Hamid Q. Pathogenesis of severe asthma. Clin Exp Allergy 2012; 42: 625– 37. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 2Lotvall J, Akdis CA, Bacharier LB et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2010; 127: 355– 60. CrossrefWeb of Science®Google Scholar 3Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol 2013; 8: 477– 512. CrossrefCASPubMedWeb of Science®Google Scholar Caption to cover illustration: miRNA biogenesis. Following the transcription of the pri-miRNA transcript (1), the pre-miRNA is excised by Drosha (2) and transported by Exportin-5 into the cytoplasm (3). Splicing of the pre-miRNA by Dicer generates the miRNA duplex (4) that contains the mature miRNA strand, which together with several accessory proteins assembles into the RISC complex (5) to enable post-transcriptional regulation of target mRNA translation (6). [See figure 1 in M. Plank et al. (981-999)]. This logo highlights the Editor's Choice articles on the cover and the first page of each of the articles. Volume43, Issue9September 2013Pages 977-977 ReferencesRelatedInformation

From bedside to bench to clinic trials: identifying new treatments for severe asthma

Asthmatics with a severe form of the disease are frequently refractory to standard medications such as inhaled corticosteroids, underlining the need for new treatments to prevent the occurrence of potentially life-threatening episodes. A major obstacle in the development of new treatments for severe asthma is the heterogeneous pathogenesis of the disease, which involves multiple mechanisms and cell types. Furthermore, new therapies might need to be targeted to subgroups of patients whose disease pathogenesis is mediated by a specific pathway. One approach to solving the challenge of developing new treatments for severe asthma is to use experimental mouse models of asthma to address clinically relevant questions regarding disease pathogenesis. The mechanistic insights gained from mouse studies can be translated back to the clinic as potential treatment approaches that require evaluation in clinical trials to validate their effectiveness and safety in human subjects. Here, we will review how mouse models have advanced our understanding of severe asthma pathogenesis. Mouse studies have helped us to uncover the underlying inflammatory mechanisms (mediated by multiple immune cell types that produce Th1, Th2 or Th17 cytokines) and non-inflammatory pathways, in addition to shedding light on asthma that is associated with obesity or steroid unresponsiveness. We propose that the strategy of using mouse models to address clinically relevant questions remains an attractive and productive research approach for identifying mechanistic pathways that can be developed into novel treatments for severe asthma.

Gender difference in allergic airway remodelling and immunoglobulin production in mouse model of asthma

Epidemiological studies have shown that the prevalence of adult asthma and severe asthma is higher in women. It has also been reported that female mice are more susceptible than males to the development of allergic airway inflammation and airway hyperresponsiveness (AHR). The influence of gender difference in the pathogenesis of severe asthma, especially airway remodelling in an animal model, has been studied rarely. We investigated gender difference in the development of airway remodelling using a long-term antigen-challenged mouse asthma model. Following ovalbumin (OVA)/alum intraperitoneal injection, male or female mice (BALB/c) were challenged with aerosolized 1% OVA on 3 days/week for 5 weeks, and differences in AHR, airway inflammation and airway remodelling between the sexes were investigated. In OVA-sensitized and OVA-challenged (OVA/OVA) female mice, eosinophils, lymphocytes, T-helper type 2 cytokines and growth factors in bronchoalveolar lavage fluid were increased compared with OVA/OVA male mice. Histological features of airway remodelling were also increased in OVA/OVA female mice. Serum total and OVA-specific immunoglobulin E (IgE) and serum IgA were significantly elevated in OVA/OVA female mice. These results indicate that female mice experience more airway remodelling compared with male mice. These results suggest the involvement of sex hormones and gender differences in cellular functions in airway remodelling.

Diesel exhaust particle induction of IL17A contributes to severe asthma (P6373)

Abstract The factors that promote IL17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEP) are a major component of traffic related air pollution and are implicated in asthma exacerbation. We assessed the impact of DEP exposure on asthma severity in asthmatic children from the Greater Cincinnati Pediatric Clinic Repository. Among high DEP-exposed children with allergic asthma, 32.2% of the children had severe asthma, compared to only 14.2% in the low DEP-exposed group. Similarly, Balb/c mice co-exposed to DEP and house dust mite extract (HDM) markedly demonstrated enhanced airway inflammation and hyperresponsiveness (AHR) compared to HDM alone. Exposure to DEP alone did not induce classic features of asthma but generated a Th17 response. DEP and HDM co-exposures enhanced pulmonary Th2 and Th17 cell numbers compared to HDM alone. High DEP-exposed children with allergic asthma had elevated serum IL17A levels compared with low DEP-exposed children. Finally, IL17A neutralization alleviated DEP-induced exacerbation of AHR. In conclusion, Th17 cells contribute to DEP-mediated exacerbation of allergen-induced asthma. Neutralization of IL17A may be a useful therapeutic strategy to counteract the asthma promoting effects of traffic related air pollution especially in severe asthmatics.

Roles of IL-22 in Allergic Airway Inflammation

IL-23- and IL-17A-producing CD4+ T cell (Th17 cell) axis plays a crucial role in the development of chronic inflammatory diseases. In addition, it has been demonstrated that Th17 cells and their cytokines such as IL-17A and IL-17F are involved in the pathogenesis of severe asthma. Recently, IL-22, an IL-10 family cytokine that is produced by Th17 cells, has been shown to be expressed at the site of allergic airway inflammation and to inhibit allergic inflammation in mice. In addition to Th17 cells, innate lymphoid cells also produce IL-22 in response to allergen challenge. Functional IL-22 receptor complex is expressed on lung epithelial cells, and IL-22 inhibits cytokine and chemokine production from lung epithelial cells. In this paper, we summarize the recent progress on the roles of IL-22 in the regulation of allergic airway inflammation and discuss its therapeutic potential in asthma.

Asthma phenotypes and endotypes

It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. In this review, we discuss the present understanding of different asthma phenotypes and endotypes, and the prospects of personalized medicine for asthma. The recognition of diverse biological backgrounds in which asthma, and particularly severe asthma, can manifest has prompted the search for refined phenotypes and endotypes in asthma. Such appreciation of the heterogeneity in asthma is also prompting clinical trials to focus on specific subgroups of asthma, as demonstrated by the clinical trial of lebrikizumab. Patients with severe asthma have asthma symptoms that are difficult to control, require high dosages of medication, and continue to experience persistent symptoms, asthma exacerbations or airflow obstruction even with aggressive therapy. Although asthma is traditionally viewed as an eosinophilic inflammatory disorder associated with a T-helper cell type 2 (Th2) immune response, recent studies have identified involvement of other effector cells, nonclassical Th2 cytokines and non-Th2 cytokines in severe asthma pathogenesis. Results of several clinical trials of anticytokine antibodies demonstrated the effectiveness of tailoring asthma treatment on the basis of an individual's biology.

Pathogenesis of severe asthma

Patients with severe asthma have asthma symptoms which are difficult to control, require high dosages of medication, and continue to experience persistent symptoms, asthma exacerbations or airflow obstruction. Epidemiological and clinical evidences point to the fact that severe asthma is not a single phenotype. Cluster analyses have identified subclasses of severe asthma using parameters such as patient characteristics, and cytokine profiles have also been useful in classifying moderate and severe asthma. The IL-4/IL-13 signalling pathway accounts for the symptoms experienced by a subset of severe asthmatics with allergen-associated symptoms and high serum immunoglobulin E (IgE) levels, and these patients are generally responsive to anti-IgE treatment. The IL-5/IL-33 signalling pathway is likely to play a key role in the disease pathogenesis of those who are resistant to high doses of inhaled corticosteroid but responsive to systemic corticosteroids and anti-IL5 therapy. The IL-17 signalling pathway is thought to contribute to 'neutrophilic asthma'. Although traditionally viewed as players in the defence mechanism against viral and intracellular bacterial infection, mounting evidence supports a role for Th1 cytokines such as IL-18 and IFN-γ in severe asthma pathogenesis. Furthermore, these cytokine signalling pathways interact to contribute to the spectrum of clinical pathological outcomes in severe asthma. To date, glucocorticoids are the most effective anti-asthma drugs available, yet severe asthma patients are typically resistant to the effects of glucocorticoids. Glucocorticoid receptor dysfunction and histone deacetylase activity reduction are likely to contribute to glucocorticoid resistance in severe asthma patients. This review discusses recent development in different cytokine signalling pathways, their interactions and steroid resistance, in the context of severe asthma pathogenesis.

Emerging roles of pulmonary macrophages in driving the development of severe asthma

Asthma is recognized as a heterogeneous disorder, although in most patients, the clinical manifestations are effectively managed with established combination therapies. However, 5-10% of asthmatics have severe asthma, which does not respond to treatment, and these patients account for >50% of asthma-related healthcare costs. New investigations into the pathogenesis of glucocorticoid resistance in severe asthma indicate that pulmonary macrophages may play central roles in promoting airway inflammation, particularly in asthma that is resistant to steroid therapy. Importantly, factors that are linked to the activation of pulmonary macrophages may contribute to glucocorticoid resistance and severe asthma. Here, we review recent advances in understanding the roles of pulmonary macrophages in the mechanisms of glucocorticoid resistance and the pathogenesis of severe asthma. We discuss the role of macrophage phenotype, infection, IFN-γ, LPS, associated signaling pathways, TNF-α, MIF, and other macrophage-associated factors. Understanding the pathogenesis of steroid-resistant severe asthma will contribute to the identification of optimal therapeutic strategies for the effective management of the disease.

120 The Features of Airway Remodeling Are More Severe in Female Mice

BackgroundEpidemiological studies have already shown that females are dominant in terms of the sex ratio of adult asthma prevalence and severe asthma. It has also been reported that female mice are more susceptible to the development of allergic airway inflammation and airway hyperresponsiveness (AHR) than males. However, there have been few reports of studies on sex difference in the pathogenesis of severe asthma, especially airway remodeling in an animal model. In this study, we investigated sex difference in formation of airway remodeling using a long-term antigen challenged asthma model.MethodsFollowing ovalbumin (OVA)/alum intraperitoneal injection, male or female mice (BALB/c) were challenged with aerosolized 1% OVA on 3 days/week for 5 weeks, and we investigated the sex difference in AHR, airway inflammation, as well as airway remodeling.ResultsIn OVA-sensitized and -challenged (OVA/OVA) female mice, AHR, the number of eosinophils and lymphocytes, as well as Th2 cytokines and growth factors in BAL fluid were increased compared with OVA/OVA male mice. On the other hand, there is no significant difference in the level of eotaxin in BAL fluid. The histological features of airway remodeling, including goblet cell hyperplasia, subepithelial fibrosis and myofibroblast hypertrophy, were also increased in OVA/OVA female mice. Moreover, serum total and OVA-specific IgE were significantly elevated in OVA/OVA female mice.ConclusionsThese results indicate that female mice are dominant in terms of forming airway remodeling as compared with male mice. The involvement of sex difference for sensitization and growth factor release in lung tissue based on inflammatory cell infiltration is indicated for the mechanism of sex difference of airway remodeling.

High Expression of IL-22 Suppresses Antigen-Induced Immune Responses and Eosinophilic Airway Inflammation via an IL-10–Associated Mechanism

Allergic inflammation in the airway is generally considered a Th2-type immune response. However, Th17-type immune responses also play important roles in this process, especially in the pathogenesis of severe asthma. IL-22 is a Th17-type cytokine and thus might play roles in the development of allergic airway inflammation. There is increasing evidence that IL-22 can act as a proinflammatory or anti-inflammatory cytokine depending on the inflammatory context. However, its role in Ag-induced immune responses is not well understood. This study examined whether IL-22 could suppress allergic airway inflammation and its mechanism of action. BALB/c mice were sensitized and challenged with OVA-Ag to induce airway inflammation. An IL-22-producing plasmid vector was delivered before the systemic sensitization or immediately before the airway challenge. Delivery of the IL-22 gene before sensitization, but not immediately before challenge, suppressed eosinophilic airway inflammation. IL-22 gene delivery suppressed Ag-induced proliferation and overall cytokine production in CD4(+) T cells, indicating that it could suppress Ag-induced T cell priming. Antagonism of IL-22 by IL-22-binding protein abolished IL-22-induced immune suppression, suggesting that IL-22 protein itself played an essential role. IL-22 gene delivery neither increased regulatory T cells nor suppressed dendritic cell functions. The suppression by IL-22 was abolished by deletion of the IL-10 gene or neutralization of the IL-10 protein. Finally, IL-22 gene delivery increased IL-10 production in draining lymph nodes. These findings suggested that IL-22 could have an immunosuppressive effect during the early stage of an immune response. Furthermore, IL-10 plays an important role in the immune suppression by IL-22.

The Role of Mast Cells in the Structural Alterations of the Airways as a Potential Mechanism in the Pathogenesis of Severe Asthma

Mast cells, traditionally regarded as effector cells of the immune system, have more recently been demonstrated to be key figures in initiating, developing and sustaining complex pathophysiological processes underlying asthma and other allergic diseases. Asthma is characterised by airway inflammation alongside a disturbance to airway physiology manifesting as variable airflow obstruction and airway hyper-responsiveness (AHR). Evidence has emerged that mast cells influence airway function by forming close intercellular relationships with different structural components of the airway wall. In asthma, mast cells are seen to localise to the airway epithelium, to mucous glands and to the airway smooth muscle (ASM). It is mast cell-ASM interaction that is most fundamental to the asthma phenotype and many mast cell mediators have been demonstrated to have important effects on ASM function. In asthma, alongside the inflammatory and physiological changes, structural changes occur to the airway wall in the form of denudation of the epithelium, goblet cell and mucous gland hyperplasia, subepithelial fibrosis, abnormal extracellular matrix (ECM) deposition, vascular proliferation and increased ASM mass. There are many ways in which mast cells can contribute to these structural changes through direct cell to cell communication and more indirectly through mediator release. Mast cells exhibit an array of diverse functions and roles and are fundamental to our current understanding of asthma pathogenesis including severe asthma. Novel targeting of mast cells and their mediators therefore should offer significant therapeutic potential in the treatment of asthma.

Pathogenesis of airway inflammation in bronchial asthma

Bronchial asthma is a chronic disorder characterized by airway inflammation, reversible airway obstruction, and airway hyperresponsiveness. Eosinophils are believed to play important roles in the pathogenesis of asthma through the release of inflammatory mediators. In refractory eosinophilic asthma, anti-IL-5 mAb reduces exacerbations and steroid dose, indicating roles of eosinophils and IL-5 in the development of severe eosinophilic asthma. Even in the absence of IL-5, it is likely that the "Th2 network", including a cascade of vascular cell adhesion molecule-1/CC chemokines/GM-CSF, can sufficiently maintain eosinophilic infiltration and degranulation. Cysteinyl leukotrienes can also directly provoke eosinophilic infiltration and activation in the airways of asthma. Therefore, various mechanisms would be involved in the eosinophilic airway inflammation of asthma. In the pathogenesis of severe asthma, not only eosinophils but also mast cells or neutrophils play important roles. Mast cells are much infiltrated to smooth muscle in severe asthma and induce airway remodeling by release of inflammatory mediators such as amphiregulin. Treatment with anti-IgE Ab, which neutralizes circulating IgE and suppresses mast cell functions, reduces asthma exacerbations in severe asthmatic patients. Furthermore, infiltration of neutrophils in the airway is also increased in severe asthma. IL-8 plays an important role in the accumulation of neutrophils and is indeed upregulated in severe asthma. In the absence of chemoattractant for eosinophils, neutrophils stimulated by IL-8 augment the trans-basement membrane migration of eosinophils, suggesting that IL-8-stimulated neutrophils could lead eosinophils to accumulate in the airways of asthma. In view of these mechanisms, an effective strategy for controlling asthma, especially severe asthma, should be considered.

JKCF1-6 Endoplasmic reticulum stress is implicated in the pathogenesis of severe asthma(Inflammatory cells in allergic diseases,Free Paper Session 1,Japan-Korea-China Joint Symposium)

JKCF1-6 Endoplasmic reticulum stress is implicated in the pathogenesis of severe asthma(Inflammatory cells in allergic diseases,Free Paper Session 1,Japan-Korea-China Joint Symposium)

S100A8/A9: a mediator of severe asthma pathogenesis and morbidity?This article is one of a selection of papers published in a special issue celebrating the 125th anniversary of the Faculty of Medicine at the University of Manitoba.

Nearly 12% of children and 6% of adults in Canada have been diagnosed with asthma. Although in most patients symptoms are controlled by inhaled steroids, a subpopulation (approximately 10%) characterized by excessive airway neutrophilia, is refractory to treatment; these patients exhibit severe disease, and account for more than 50% of asthma health care costs. These numbers underscore the need to better understand the biology of severe asthma and identify pro-asthma mediators released by cells, such as neutrophils, that are unresponsive to common steroid therapy. This review focuses on a unique protein complex consisting of S100A8 and S100A9. These subunits belong to the large Ca2+-binding S100 protein family and are some of the most abundant proteins in neutrophils and macrophages. S100A8/A9 is a damage-associated molecular pattern (DAMP) protein complex released in abundance in rheumatoid arthritis, inflammatory bowel disease, and cancer, but there are no definitive studies on its role in inflammation and obstructive airways disease. Two receptors for S100A8/A9, the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), are expressed in lung. TLR4 is linked with innate immunity that programs local airway inflammation, and RAGE participates in mediating fibroproliferative remodeling in idiopathic pulmonary fibrosis. S100A8/A9 can induce cell proliferation, or apoptosis, inflammation, collagen synthesis, and cell migration. We hypothesize that this capacity suggests S100A8/A9 could underpin chronic airway inflammation and airway remodeling in asthma by inducing effector responses of resident and infiltrating airway cells. This review highlights some key issues related to this hypothesis and provides a template for future research.

Isotype and IgG Subclass Distribution of Autoantibody Response to Alpha-enolase Protein in Adult Patients with Severe Asthma

PurposeA possible involvement of autoimmune mechanism in the pathogenesis of bronchial asthma has been proposed. Recently, alpha-enolase protein was identified as a major autoantigen recognized by circulating IgG autoantibodies in patients with severe asthma. To evaluate a possible pathogenetic significance of these autoantibodies in severe asthma, isotype (IgG, IgA, IgM, and IgE) and IgG subclass (IgG1, IgG2, IgG3, and IgG4) distributions of autoantibodies to recombinant human alpha-enolase protein were analyzed.Patients and MethodsWe examined serum samples from 10 patients with severe asthma and 7 patients with mild-to-moderate asthma, and 5 healthy controls by immunoblot analysis. Severe asthma was defined as patients having at least 1 severe asthmatic exacerbation requiring an emergency department visit or admission in the last year despite continuous typical therapies.ResultsIgG1 was the predominant IgG subclass antibody response to alpha-enolase protein in patients with severe asthma. IgG1 autoantibody to alpha-enolase protein was detected in 7 of 10 patients with severe asthma (70%), 1 of 7 patients with mild-to-moderate asthma (14.3%), and none of 5 healthy controls (0%) (chi-square test; p < 0.05). IgA, IgM, and IgE autoantibodies to alpha-enolase protein could not be detected in patients with severe asthma.ConclusionIgG1 subclass was the predominant type of autoantibody response to alpha-enolase protein in patients with severe asthma, suggests a possibility of IgG1 autoantibody-mediated complement activation in the pathogenesis of severe asthma.

85-kDa cytosolic phospholipase A2 group IVα gene promoter polymorphisms in patients with severe asthma: a gene expression and case–control study

Cytosolic phospholipase A(2) (cPLA(2)) group IValpha is a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. cPLA(2)(-/-) mice have reduced allergen-induced bronchoconstriction and bronchial hyperresponsiveness. The goal of this study was to investigate polymorphisms of the (CA)(n) and (T)(n) microsatellites and surrounding regions in the cPLA(2)alpha gene promoter. We analysed the cPLA(2) promoter regions containing (CA)(n) and (T)(n) repeats in 87 patients with severe asthma and in 48 control subjects by bidirectional sequencing. Functional studies were performed utilizing reporter genes derived from subjects with varying numbers of these repeats, and on constructs with a series of deletions. We found that the (CA)(n) and (T)(n) regions are polymorphic and that constructs with CA or T repeats or CA and T repeats deleted revealed, respectively, a 41.8 +/- 7%, 22.3 +/- 5% and 100 +/- 20% increase in reporter gene activity. A lower number of CA or T repeats caused higher cPLA(2) promoter luciferase activity. The group of shorter alleles of the (CA)(n) microsatellite region (n = 12-18) (P(cor) = 0.00006), and the group of shorter alleles of (T)(n) repeats region (n = 17-38) (P(cor) = 0.0039) occurred significantly more often in patients with severe asthma. We also found novel SNPs in positions -292 C > G, -185 A > C, -180 T > C and -165 A > C. Two of them were associated with the severe asthma phenotype: -180T allele (P(cor) = 0.03996) and -185 A allele (P(cor) = 0.03966). These results demonstrate that (CA)(n) and (T)(n) repeats may have an influence on cPLA(2) transcription which might play a role in severe asthma pathogenesis.

T-bet inhibits both T H2 cell–mediated eosinophil recruitment and T H17 cell–mediated neutrophil recruitment into the airways

Previous studies have shown that mice lacking T-bet, a critical transcription factor for T(H)1 cell differentiation, spontaneously develop airway inflammation with intense eosinophil infiltrates. However, the mechanism underlying T-bet-mediated inhibition of allergic airway inflammation is still unknown. To determine the regulatory role of T-bet in antigen-induced allergic airway inflammation. We examined the role of T-bet in antigen-induced allergic airway inflammation using T-bet(-/-) mice on a BALB/c background that did not develop spontaneous airway inflammation. We also examined the role of T-bet expression of CD4(+) T cells in airway inflammation by adoptive transfer experiments. We found that antigen-induced eosinophil recruitment, goblet cell hyperplasia, and T(H)2 cytokine production in the airways were enhanced in T-bet(-/-) mice. However, in the absence of signal transducer and activator of transcription 6 (STAT6), T-bet deficiency could not induce the antigen-induced eosinophilic airway inflammation. Adoptive transfer of T-bet(-/-) or T-bet(+/+) CD4(+) T cells to T-bet(-/-)Rag-2(-/-) mice revealed that the expression of T-bet in CD4(+) T cells was vital for the inhibition of antigen-induced eosinophilic airway inflammation. Interestingly, antigen-induced neutrophil recruitment in the airways was also enhanced in T-bet(-/-) mice. Moreover, T-bet(-/-) CD4(+) T cells preferentially differentiated into IL-17-producing cells that mediated neutrophilic airway inflammation. T-bet inhibits both T(H)2 cell-mediated eosinophilic inflammation and T(H)17 cell-mediated neutrophilic inflammation in the airways. The dysfunction of T-bet may be involved in the pathogenesis of severe asthma, in which accumulation of neutrophils as well as eosinophils in the airways is a hallmark of disease.

A variant of the myosin light chain kinase gene is associated with severe asthma in African Americans

Asthma is a complex phenotype influenced by environmental and genetic factors for which severe irreversible structural airway alterations are more frequently observed in African Americans. In addition to a multitude of factors contributing to its pathobiology, increased amounts of myosin light chain kinase (MLCK), the central regulator of cellular contraction, have been found in airway smooth muscle from asthmatics. The gene encoding MLCK (MYLK) is located in 3q21.1, a region noted by a number of genome-wide studies to show linkage with asthma and asthma-related phenotypes. We studied 17 MYLK genetic variants in European and African Americans with asthma and severe asthma and identified a single non-synonymous polymorphism (Pro147Ser) that was almost entirely restricted to African populations and which was associated with severe asthma in African Americans. These results remained highly significant after adjusting for proportions of ancestry estimated using 30 unlinked microsatellites (adjusted odds ratio: 1.76 [95% confidence interval, CI: 1.17-2.65], p = 0.005). Since all common HapMap polymorphisms in approximately 500 kb contiguous regions have low-to-moderate linkage disequilibrium with Pro147Ser, we speculate that this polymorphism is causally related to the severe asthma phenotype in African Americans. The association of this polymorphism, located in the N-terminal region of the non-muscle MLCK isoform, emphasizes the potential importance of the vascular endothelium, a tissue in which MLCK is centrally involved in multiple aspects of the inflammatory response, in the pathogenesis of severe asthma. This finding also offers a possible genetic explanation for some of the more severe asthma phenotype observed in African American asthmatics.

Blood neutrophil activation markers in severe asthma: lack of inhibition by prednisolone therapy

BackgroundNeutrophils are increased in the airways and in induced sputum of severe asthma patients. We determined the expression of activation markers from circulating neutrophils in severe asthma, and their supressibility by corticosteroids.MethodsWe compared blood neutrophils from mild, moderate-to-severe and severe steroid-dependent asthma, and non-asthmatics (n = 10 each). We examined the effect of adding or increasing oral prednisolone (30 mg/day;1 week).ResultsFlow cytometric expression of CD35 and CD11b, but not of CD62L or CD18, was increased in severe asthma. F-met-leu-phe increased CD11b, CD35 and CD18 and decreased CD62L expression in all groups, with a greater CD35 increase in severe asthma. In severe steroid-dependent asthma, an increase in prednisolone dose had no effect on neutrophil markers particularly CD62L, but reduced CD11b and CD62L on eosinophils. Phorbol myristate acetate-stimulated oxidative burst and IL-8 release by IL-1β, lipopolysaccharide and GM-CSF in whole blood from mild but not severe asthmatics were inhibited after prednisolone. There were no differences in myeloperoxidase or neutrophil elastase release from purified neutrophils.ConclusionBecause blood neutrophils in severe asthma are activated and are not inhibited by oral corticosteroids, they may be important in the pathogenesis of severe asthma.

Inflammatory events in severe acute asthma

Severe acute asthma can be induced by different triggers, allergens, irritants, viruses, etc., which induce inflammation and provoke acute bronchoconstriction. Inflammatory cells, such as activated eosinophils and neutrophils identified in sputum and bronchial lavages (BL) in severe acute asthma from children and adults are associated with increased levels of IL-5, IL-8, and of proinflammatory mediators. Viruses, but also endotoxin or allergen exposure, are able to recruit neutrophils, via an IL-8 production by activated macrophages or epithelial cells. Together, these inflammatory mediators are responsible for the diffuse bronchial inflammation, which involve large and small airways. Activated T cells may also be related to the pathogenesis of severe asthma. An aberrant CD8+ T lymphocyte response in bronchi, with a cytotoxic activity has been associated with fatal asthma. Moreover, the persistence of inflammatory cells in bronchi, particularly neutrophils, which respond poorly to corticosteroids, could be in part responsible for the epithelial damage, the extensive mucus plugging, and the abnormalities of epithelial and endothelial permeability which are associated with severe acute asthma. Further studies are necessary to better identify the implication of this increased bronchial permeability in the persistence of high levels of airway resistance, particularly in patients with status asthmaticus.