Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D04296 (Asthma)
 25,733 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Asthma is a multifactorial and complex disease in which allergic factors and non-allergic triggers interact and result in bronchial obstruction and inflammation. Allergenic sensitization is important in the development of asthma and, although links between inhalant allergy and asthma have been known for many years, they have recently been re-emphasized. Indoor allergens are associated with asthma prevalence, severity and exacerbations whereas outdoor allergens such as pollens are associated with exacerbations. Moreover, there is a link between total IgE and asthma which appears to be independent of allergen sensitization. One of the typical aspects of airway inflammation of asthma is the infiltration of the airway wall by T helper type 2 (Th2) cells. These cells are attracted to inflammatory sites by adhesion molecules and chemokines among which CCR3 and CXCR4 receptors appear to be of importance. Differentiation of B cells into IgE-secreting plasma cells is a complex cascade of events in which cytokines play a crucial role. Both IL-4 and IL-13 are inducing IgE synthesis whereas IFN-gamma and IL-12 are blocking IgE synthesis. IgE production by B cells not only requires the presence of IL-4 or IL-13, but also a physical interaction between T and B cells, involving a number of surface and adhesion molecules such as CD40-CD40L and CD28/CD80. Production of TH2-cytokines is not restricted to T cells as basophils and mast cells can produce them indicating that these cells may be of importance in the synthesis of IgE.
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PMID:The role of IgE in asthma. 998 55

Asthma is characterized by a 50- to 100-fold increase in the number of eosinophils relative to neutrophils in the bronchial mucosa. This increase is not the result of a single molecular event but of the cumulative and sequential effects of several approximately 4-fold increases in selective eosinophil versus neutrophil migration, occurring at a number of stages in the life cycle of the eosinophil. These steps include (1) effects on the bone marrow, mediated principally by IL-5, which result in a 4-fold increase in circulating eosinophils, (2) selective tethering of eosinophils to venular endothelium through the combined effects of P-selectin/P-selectin glycoprotein ligand 1 and very late activation antigen-4/vascular cell adhesion molecule-1, which has the potential for an up to 10-fold increase in eosinophil versus neutrophil adhesion, (3) selective chemotaxis under the influence of CC chemokines, and (4) prolonged survival, again mediated by IL-5. These events are integrated and directed by allergen-specific T(H)2 lymphocytes through the generation of IL-5, IL-4, and IL-13. The implications of this multistep process are that antagonists of IL-5, very late activation antigen-4, P-selectin glycoprotein ligand 1, and CCR3 as well as IL-4 and IL-13 each have the potential to markedly inhibit eosinophil recruitment in asthma.
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PMID:Molecular basis for selective eosinophil trafficking in asthma: A multistep paradigm. 1055 Jul 33

Cytokines are glycoproteins that are secreted and that regulate immunologic inflammation. The cytokine system is characterized by much redundancy and cross-reactivity. Of the more than 100 cytokines that have been identified, interleukin-5 (IL-5) and the chemokine (chemotactic cytokine), eotaxin, are the most selective for cells of eosinophilic origin. Because of this relative specificity, and because of their important immunoregulatory roles, IL-5, eotaxin, and their receptors IL-5R and CCR3 are potential targets for non-glucocorticosteroid pharmacological treatment of eosinophilic inflammation.
Allergy Asthma Proc
PMID:Cytokines: regulators of eosinophilic inflammation. 1095 85

Whole genome scan analyses have revealed that chromosomal region 3p21-24, which contains a gene cluster of CC chemokine receptors such as CCR3, is possibly linked to asthma. Because CCR3 ligands play a pivotal role in the selective recruitment and activation of inflammatory cells in the asthmatic airway, the authors examined whether there is any association between asthma and the CCR3 gene polymorphisms. Three polymorphisms were identified using the single stranded conformational polymorphism method in Japanese (Asian) and British (Caucasian) subjects; one silent mutation T51C and two missense mutations G824A and T971C. These polymorphisms were examined in 391 Japanese subjects (210 asthmatics and 181 nonasthmatic controls) and 234 British subjects (142 asthmatics and 92 nonasthmatic controls). Asthma diagnosis was based on episodic symptoms, documented wheeze, and the presence of reversible airflow limitation. CCR3 T51C demonstrated a significant association with the diagnosis of asthma in the British population (odds ratio 2.35, p<0.01), but not in the Japanese population. Multiple logistic regression analysis also showed that CCR3 T51C was associated with asthma (odds ratio 2.83, p < 0.02), independent of atopic phenotypes such as high levels of total or house dust mite-specific immunoglobulin-E in serum. In conclusion, a significant association between asthma and CCR3 T51C polymorphism localized on chromosome 3p21 was found.
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PMID:Genetic polymorphisms of CC chemokine receptor 3 in Japanese and British asthmatics. 1130 56

Asthma is characterised by a 50-fold increase in the number of eosinophils relative to neutrophils in the bronchial mucosa. This is the result of the cumulative and sequential effects of several, approximately fourfold, increases in selective eosinophil versus neutrophil migration occurring at a number of stages in the life cycle of the eosinophil. These events, which are integrated and directed by allergen-specific T helper 2 lymphocytes through the generation of interleukin (IL)-5, IL-4 and IL-13, include: effects on the bone marrow, mediated principally by IL-5, which result in a fourfold increase in circulating eosinophils selective tethering of eosinophils to venular endothelium through the combined effects of P-selectin/P-selectin glycoprotein ligand (PSGL)-1 and very late activation antigen (VLA)-4/vascular cell adhesion molecule-1, which has the potential for an up to tenfold increase in eosinophil versus neutrophil adhesion selective chemotaxis under the influence of CC chemokines prolonged survival, again mediated by IL-5. The implications of this multistep process are that antagonists of IL-5, VLA-4, PSGL-1 and CC chemokine receptor 3, as well as IL-4 and IL-13, each have the potential markedly to inhibit eosinophil recruitment in asthma.
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PMID:Eosinophil trafficking in asthma. 1144 18

Asthma is characterized by the accumulation of activated T cells and eosinophils within the airway. Eosinophils derive from CD34(+) bone marrow progenitor cells under the influence of hematopoietic growth factors, subsequently migrating to the airways under the cooperative influence of interleukin (IL)-5 and chemokines, including eotaxin. We compared the relative effects of systemic versus local IL-5 on progenitor-cell mobilization and mature eosinophil phenotype by using flow cytometry, following the administration of intravenous (2 microg) or inhaled (15 microg) IL-5 to nine patients with mild asthma. Intravenous IL-5 induced a rapid reduction in circulating eosinophil counts followed by prolonged blood eosinophilia. Both intravenous (p < 0.002) and inhaled (p < 0.05) IL-5 significantly increased CD34(+)/CD45(+) lymphoblastoid eosinophil progenitors. Intravenous IL-5 increased mature eosinophil CCR3 expression from a baseline mean fluorescence intensity (MFI) of 658 +/- 51.7 to 995 +/- 93.2 at 24 h (p < 0.05), but had no effect on interleukin-5 receptor subunit alpha or CD11b expression. Lymphocyte CCR3 MFI was increased by intravenous IL-5 from 38.5 +/- 13.6 at baseline to 73.6 +/- 14.3 at 24 h (p < 0.05). Systemic IL-5 increased circulating eosinophil progenitors, suggesting a key role for systemic IL-5 in eosinophil mobilization. Further, IL-5 causes terminal maturation of the eosinophil by increasing CCR3 expression, potentially affecting CCR3-dependent chemotaxis by eosinophils and lymphocytes.
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PMID:Interleukin-5 induces CD34(+) eosinophil progenitor mobilization and eosinophil CCR3 expression in asthma. 1218 32

Asthma is one of the most common chronic diseases in childhood; it is caused by a complex interaction between genetic factors and exposure to environmental allergens and irritants. Previous studies using the candidate gene approach showed that asthma was linked to a number of susceptibility genetic loci in Caucasian subjects. There are, however, only a few studies on asthma predisposition genes in the Chinese population. We studied the distribution of allele frequencies of I50V for the interleukin-4 receptor, two polymorphisms in intron 2 and exon 7 for the high-affinity IgE receptor (Fc epsilon RI-beta), R16G and E27Q for the beta(2)-adrenoceptor,and R275Q (824G/A) for CC chemokine receptor 3 in Chinese children.Seventy-six patients, with a mean age of 10.6 years, and 70 age- and sex-matched controls, were studied. Significantly more subjects in the asthma group had specific IgE antibodies against environmental allergens (P < 0.0001; odds ratio, 9.82). Genotyping of the six genetic markers showed that none of the six polymorphisms was associated with asthma in this cohort. The allele frequencies of I50V, R16G, and E27Q in our population were similar to those published for Asian subjects but not Caucasians. The R275Q substitution was a rare finding in our study and in the published reports. Our results demonstrate ethnic differences in polymorphisms of atopy candidate genes. Additional studies involving larger samples are required to investigate the association between asthma or atopy and the genotypes studied to date in Chinese children.
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PMID:Distribution in allele frequencies of predisposition-to-atopy genotypes in Chinese children. 1242 39

Asthma is characterized by infiltration of the airway wall with eosinophils. Although eosinophils are considered to be effector cells, recent studies have reported their ability to activate primed Th2 cells. In this study, we investigated whether eosinophils are capable of presenting Ag to unprimed T cells in draining lymph nodes (DLN) of the lung and compared this capacity with professional dendritic cells (DC). During development of eosinophilic airway inflammation in OVA-sensitized and challenged mice, CCR3(+) eosinophils accumulated in the DLN. To study their function, eosinophils were isolated from the bronchoalveolar lavage fluid of mice by sorting on CCR3(+)B220(-)CD3(-)CD11c(dim) low autofluorescent cells, avoiding contamination with other APCs, and were intratracheally injected into mice that previously received CFSE-labeled OVA TCR-transgenic T cells. Eosinophils did not induce divisions of T cells in the DLN, whereas DC induced on average 3.7 divisions in 45.7% of T cells. To circumvent the need for Ag processing or migration in vivo, eosinophils were pulsed with OVA peptide and were still not able to induce T cell priming in vitro, whereas DC induced vigorous proliferation. This lack of Ag-presenting ability was explained by the very weak expression of MHC class II on fresh eosinophils, despite expression of the costimulatory molecules CD80 and ICAM-1. This investigation does not support any role for airway eosinophils as APCs to naive T cells, despite their migration to the DLN at times of allergen exposure. DC are clearly superior in activating T cells in the DLN of the lung.
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PMID:Airway eosinophils accumulate in the mediastinal lymph nodes but lack antigen-presenting potential for naive T cells. 1450 Jun 30

Asthma is a serious health problem and during the last decade various experimental models of asthma have been developed to study the pathogenesis of this disease. In this study we describe a new mouse model of asthma that uses the spores of Alternaria alternata and Cladosporium herbarum, two allergenic molds recognized as common inducers of rhinitis and asthma in humans. Here we demonstrate that A. alternata and C. herbarum spores are immunogenic when injected into BALB/c mice, and induce the production of specific IgM and IgG1 antibodies and strongly increase IgE serum levels. To induce the allergic response, mice were sensitized by two intraperitoneal (i.p.) injections and then intranasaly (i.n.) challenged with A. alternata and C. herbarum spores. Bronchoalveolar lavages (BALs) from these mice contained numerous macrophages, neutrophils, eosinophils and lymphocytes whereas neutrophils were the predominant BAL inflammatory cells in nonsensitized mice. Histological studies demonstrated an influx of eosinophils in peri-vascular and peri-bronchial areas and the presence of numerous epithelial goblet cells only in sensitized mice. Increased expression of mRNA specific for various chemokines (eotaxin, MIP-1alpha, MIP-2) and chemokine receptors (CCR-1, CCR-2 and CCR-5) was observed in the lungs of nonsensitized mice challenged with the spores. Expression of CCR-3 mRNA in the lungs and Th2 cytokine (IL-4, IL-5 and IL-13) secretion in the BAL was additionally observed in sensitized and challenged mice. Finally we demonstrate through whole-body plethysmography that mold spore sensitization and challenge induce the development of an airway hyperreactivity in response to nebulized methacholine.
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PMID:A new mouse model of lung allergy induced by the spores of Alternaria alternata and Cladosporium herbarum molds. 1565 16

Chemokines and chemokine receptors are part of a complex network of molecules that play a key role in leukocyte migration and activation. The chemokine family role is crucial in the immune system, orchestrating innate and acquired immune responses, but also in allergic inflammation. A subset of chemokines, including CCL11, CCL24, CCL26, CCL7, CCL13, CCL17, and CCL22 is highly expressed by the three main cell types involved in allergic inflammation: eosinophils, basophils, and Th2 lymphocytes. In vitro and in vivo experimental studies in murine models of asthma as well as evidence from patients with asthma confirm the role of these chemokines and their receptors, including CCR3, CCR4, and CCR8, establishing a subset of chemokine/chemokine receptor that is potentially important in allergic inflammation. Recent data support the concept that interfering with chemokines or chemokine receptors represents a new approach in allergy therapy. However, even if some of them have been shown to be effective in animal models, none is as yet used in human patients.
Curr Allergy Asthma Rep 2005 Mar
PMID:New chemokine targets for asthma therapy. 1568 17


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