Eosinophil Inflammation in Asthma

Bousquet, Jean; Chanez, Pascal; Vignola, Antonio M.; Lacoste, Jean-Yves; Michel, François

doi:10.1164/ajrccm/150.5_pt_2.s33

Cited by 89 publications

(48 citation statements)

References 92 publications

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“…The close associations of all the outcomes investigated with physician-diagnosed asthma were consistent with previous studies. 2,3,[5][6][7] The relationship of the outcomes investigated to age and gender was similar to that found in other population-based studies of Caucasians. [23][24][25][26][27][28] The smoking rates for parents and offspring were similar to those in the Australian general population.…”

Section: Discussionsupporting

confidence: 84%

“…3 Variably reduced spirometric measures such as the forced expiratory volume in one second (FEV 1 ) and the forced vital capacity (FVC) are closely but not specifically associated with asthma and atopy. 4,5 Asthma is also typified by elevated blood eosinophil counts 6 and by non-specific increased airway responsiveness (AR) to inhaled agonists such as histamine or methacholine, which can be quantified by measuring the reduction of expiratory airflow following increasing doses of these agents. 7 Asthma is a genetically complex disease with poorly defined determinants.…”

Section: Introductionmentioning

confidence: 99%

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Familial aggregation and heritability of asthma-associated quantitative traits in a population-based sample of nuclear families

et al. 2000

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Asthma is a common, genetically complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, variably reduced spirometric measures and increased airway responsiveness (AR) are physiological traits which are characteristic of asthma. We investigated the genetic and environmental components of variance of serum total and specific IgE levels, blood eosinophil counts, the forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC), and AR in an Australian population-based sample of 232 Caucasian nuclear families. With the exception of FVC levels, all traits were closely associated with clinical asthma in this population. Log e total serum IgE levels had a narrow-sense heritability (h 2 N ) of 47.3% (SE = 10.0%). Specific serum IgE levels against house dust mite and Timothy grass, measured as a RAST Index, had a h 2 N of 33.8% (SE = 7.3%). FEV 1 levels had a h 2 N of 6.1% (SE = 11.6%), whilst FVC levels had a h 2 N of 30.6% (SE = 26.8%). AR, quantified by the log e dose-response slope to methacholine (DRS), had a h 2 N of 30.3% (SE = 12.3%). These data are consistent with the existence of important genetic determinants of the pathophysiological traits associated with asthma. Our study suggests that total and specific serum IgE levels, blood eosinophil counts and airways responsiveness to inhaled agonist are appropriate phenotypes for molecular investigations of the genetic susceptibility to asthma.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Familial aggregation and heritability of asthma-associated quantitative traits in a population-based sample of nuclear families

et al. 2000

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“…1,4,13,33 The relationships of these phenotypes with age, gender and smoking habits agreed well with those found in other studies (see Baldacci et al 28 for a review).…”

Section: Discussionsupporting

confidence: 89%

Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands

et al. 2004

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Asthma is a complex disease, associated with biological and physiological phenotypes including immunoglobulin E (IgE) levels, sum of positive skin prick tests to allergens (SPTQ), eosinophil counts (EOS) and percent predicted forced expiratory volume in 1 s (%FEV 1 ). We investigated the patterns of familial correlations and the inter-relationships of these four quantitative phenotypes, using the general class D regressive model, in 320 French EGEA nuclear families ascertained through 204 offspring (set A) and 116 parents (set B). Familial correlations of IgE and SPTQ were consistent with a model including no spouse correlation and equal parent -offspring and sib -sib correlations (q PO ¼ q SS ¼ 0.25 for IgE and 0.15 for SPTQ), this model being compatible with an additive polygenic model in the whole sample and the two family subsets A and B. Different patterns of familial correlations of EOS and %FEV 1 were observed in these two sets. In set A, the best fitting model included no spouse correlation and equality of parent -offspring and sib -sib correlations (q PO ¼ q SS ¼ 0.14 for EOS and 0.23 for %FEV 1 ). In set B, EOS had only a significant q SS of 0.28, while %FEV 1 had significant q MO of 0.28 and q SS of 0.16. Analysis of shared familial determinants between these phenotypes indicated an overlap of at most 30% in q FO for IgE and SPTQ and in both q FO and q MO for IgE and EOS, while determinants of %FEV 1 and atopy-related phenotypes appear distinct. These results may have implications for further linkage and association studies with genetic markers.

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“…This may be of some significance, as loss of AChE activity would be expected to lead to increased neurotransmission via ACh and augment the effect of the other changes seen in this system (i.e., increased cholinergic activity). There have been prior studies in a number of animal models of loss of function of acetylcholinesterase (27,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). The observation of decreased acetylcholinesterase activity in the context of a modest increase in acetylcholinesterase protein expression may seem contradictory.…”

Section: Discussionmentioning

confidence: 99%

Eosinophil-Mediated Cholinergic Nerve Remodeling

Durcan

Costello²,

McLean³

et al. 2006

Am J Respir Cell Mol Biol

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Eosinophils are observed to localize to cholinergic nerves in a variety of inflammatory conditions such as asthma, rhinitis, eosinophilic gastroenteritis, and inflammatory bowel disease, where they are also responsible for the induction of cell signaling. We hypothesized that a consequence of eosinophil localization to cholinergic nerves would involve a neural remodeling process. Eosinophil co-culture with cholinergic IMR32 cells led to increased expression of the M 2 muscarinic receptor, with this induction being mediated via an adhesion-dependent release of eosinophil proteins, including major basic protein and nerve growth factor. Studies on the promoter sequence of the M 2 receptor indicated that this induction was initiated at a transcription start site 145 kb upstream of the gene-coding region. This promoter site contains binding sites for a variety of transcription factors including SP1, AP1, and AP2. Eosinophils also induced the expression of several cholinergic genes involved in the synthesis, storage, and metabolism of acetylcholine, including the enzymes choline acetyltransferase, vesicular acetylcholine transferase, and acetylcholinesterase. The observed eosinophil-induced changes in enzyme content were associated with a reduction in intracellular neural acetylcholine but an increase in choline content, suggesting increased acetylcholine turnover and a reduction in acetylcholinesterase activity, in turn suggesting reduced catabolism of acetylcholine. Together these data suggest that eosinophil localization to cholinergic nerves induces neural remodeling, promoting a cholinergic phenotype.

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Eosinophil Inflammation in Asthma

Cited by 89 publications

References 92 publications

Familial aggregation and heritability of asthma-associated quantitative traits in a population-based sample of nuclear families

Familial aggregation and heritability of asthma-associated quantitative traits in a population-based sample of nuclear families

Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands

Eosinophil-Mediated Cholinergic Nerve Remodeling

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