Epithelium dysfunction in asthma

Holgate, Stephen T.

doi:10.1016/j.jaci.2007.10.025

Cited by 441 publications

(349 citation statements)

References 130 publications

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“…Reciprocal signaling from epithelial to mesenchymal cells in the EMTU is considered important for normal airway homeostasis, and alterations in the EMTU may result in aberrant autocrine and paracrine responses that could promote subepithelial fibrosis in asthma (25,26). Relatively few mediators of epithelial mesenchymal communication have been studied in airway disease models, but IL-1β, secreted by epithelial cells undergoing squamous differentiation, can induce a fibrotic response in adjacent airway fibroblasts (27).…”

Section: Mmp-9mentioning

confidence: 99%

Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma

Sidhu

Yuan

Innes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

353

303

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Periostin is considered to be a matricellular protein with expression typically confined to cells of mesenchymal origin. Here, by using in situ hybridization, we show that periostin is specifically up-regulated in bronchial epithelial cells of asthmatic subjects, and in vitro, we show that periostin protein is basally secreted by airway epithelial cells in response to IL-13 to influence epithelial cell function, epithelial-mesenchymal interactions, and extracellular matrix organization. In primary human bronchial epithelial cells stimulated with periostin and epithelial cells overexpressing periostin, we reveal a function for periostin in stimulating the TGF-β signaling pathway in a mechanism involving matrix metalloproteinases 2 and 9. Furthermore, conditioned medium from the epithelial cells overexpressing periostin caused TGF-β-dependent secretion of type 1 collagen by airway fibroblasts. In addition, mixing recombinant periostin with type 1 collagen in solution caused a dramatic increase in the elastic modulus of the collagen gel, indicating that periostin alters collagen fibrillogenesis or cross-linking and leads to stiffening of the matrix. Epithelial cell-derived periostin in asthma has roles in TGF-β activation and collagen gel elasticity in asthma.airway fibrosis | fibroblasts | epithelial to mesenchymal transition | MMP-2 | MMP-9

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Section: Mmp-9mentioning

confidence: 99%

Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma

Sidhu

Yuan

Innes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

353

303

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“…Increased inflammatory response in epithelium plays an important role in development of asthma (27). We first assessed whether YKL-40 increased the production of inflammatory mediators in HBECs (BEAS-2B and HBECs).…”

Section: Stimulation Of Ykl-40 Increased Il-8 Production In Hbecsmentioning

confidence: 99%

YKL-40 Induces IL-8 Expression from Bronchial Epithelium via MAPK (JNK and ERK) and NF-κB Pathways, Causing Bronchial Smooth Muscle Proliferation and Migration

Tang

Sun

Shi

et al. 2013

The Journal of Immunology

105

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Recently, the serum levels of YKL-40, a chitinase-like glycoprotein, have been shown to be significantly elevated in asthmatics and are associated with asthma severity. Although these studies raise the possibility that YKL-40 may influence asthma, the mechanisms remain unknown. This study firstly investigated the mechanisms involved in YKL-40–mediated inflammation in human bronchial epithelial cells (HBECs) and analyzed the soluble factors secreted by bronchial epithelial cells exposed to YKL-40 that were responsible for increasing proliferation and migration of primary normal human bronchial smooth muscle cells (BSMCs). YKL-40–induced inflammation was assayed in two HBECs (BEAS-2B cell line and primary HBECs). In addition, we treated BEAS-2B cells and HBECs with YKL-40 and added the conditioned culture media to BSMCs. The proliferation and migration of BSMCs were determined by premixed WST-1 cell proliferation reagent (Clontech Laboratories) and QCM chemotaxis migration assay (Millipore), respectively. Bronchial epithelial cells treated with YKL-40 resulted in a significant increase of IL-8 production, which was dependent on MAPK (JNK and ERK) and NF-κB pathways activation. YKL-40–induced IL-8 was found to further stimulate proliferation and migration of BSMCs, and the effects were inhibited after neutralizing IL-8. Through investigating the interaction of airway epithelium and smooth muscle, our findings implicate that YKL-40 may be involved in the inflammation of asthma by induction of IL-8 from epithelium, subsequently contributing to BSMC proliferation and migration. Moreover, inhibition of IL-8 signaling is a potential therapeutic target for YKL-40–induced inflammation and remodeling of asthma.

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“…Our postulation is supported by the hypothesis that not the dysregulated immune response, but the inherently abnormal respiratory epithelium of asthmatics and the reactivation of the epithelial-mesenchymal trophic unit leading to pathological airway wall remodeling has a major role in the disease. 16,17 Another interesting finding was the distinct partition of genes between adult and child asthma. The association of LTC4S, AAA1 and CCL5 specifically in the child samples might reflect the differing etiopathogenetic background of childhood asthma.…”

Section: Discussionmentioning

confidence: 99%

Replication of genetic association studies in asthma and related phenotypes

et al. 2010

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In asthma genetics, the association of highly replicated susceptibility genes lacks consistency across populations. To identify genuine associations, we investigated the reproducibility of the 23 most promising asthma and asthma-related candidate genes in a moderately sized sample from the Japanese population. We compared the frequency of 33 polymorphisms in unrelated cases and controls and tested for their association with asthma, atopy and serum total IgE levels using allele frequency, codominant, dominant and recessive genotype models. On the basis of the consistency of our findings with previous metaanalyses and large replication studies, IL13, TNF, ADAM33, IL4RA and TBXA2R might represent common major asthma and asthma-related trait genes. Individual gene assessment was extended to the interactions between two polymorphisms using our original method. Interactions between TBXA2R and ADAM33, and IL4RA and C3 were suggested to increase the risk for childhood and all asthma (adult and childhood asthma combined). The confirmation of previously reported associations between gene polymorphisms and phenotypes was problematic when as few as several hundred samples per group were used. Stratification of the subjects by environmental factors or other confounding factors may be necessary to improve the sensitivity and reliability of association results. Keywords: association; asthma; atopy; polymorphism; replication INTRODUCTIONAsthma is a heritable trait 1 and investigations to determine the genetic components underlying asthma using linkage mapping and the candidate gene approach have been carried out. By 2006, more than 100 genes were associated with asthma and asthma-related phenotypes; 2 25 of these genes have been replicated in more than six independent association studies. In 2008, this list was complemented with an additional three genes, FLG, NAT2 and CCL15. 3 However, no single polymorphic marker or gene locus has been unanimously labeled as a strong and independent genetic determinant of asthma, and the results for the highly replicated genes have been inconsistent across the tested populations. 3 To identify true associations, it is of critical importance to comprehensively replicate the initial finding. 4 To this aim, we investigated whether the 23 most replicated genes for asthma and asthma-related phenotypes were positively associated with extrinsic childhood and adult asthma, atopy and total serum IgE levels in a moderately sized sample drawn from the Japanese population.We also tested eight genes that were significantly associated with asthma in our subjects: IL13, 5 TBXA2R, 6 GSTP1, 7 ADAM33, 8 MMP9, 9 IL12B, 10 C3 11 and SOCS1. 12 The re-evaluation of these associations is

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Epithelium dysfunction in asthma

Cited by 441 publications

References 130 publications

Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma

Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma

YKL-40 Induces IL-8 Expression from Bronchial Epithelium via MAPK (JNK and ERK) and NF-κB Pathways, Causing Bronchial Smooth Muscle Proliferation and Migration

Replication of genetic association studies in asthma and related phenotypes

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