Defective epithelial barrier function in asthma

Chang, Xiao; Puddicombe, Sarah M.; Field, Sarah A.; Haywood, Joel; Broughton-Head, Victoria J.; Puxeddu, Ilaria; Haitchi, Hans Michael; Vernon-Wilson, Elizabeth; Sammut, David; Bedke, Nicole; Cremin, Catherine; Sones, Jody; Djukanović, Ratko; Howarth, Peter H.; Collins, Jane; Holgate, Stephen T.; Monk, Phillip; Davies, Donna E.

doi:10.1016/j.jaci.2011.05.038

Cited by 503 publications

(311 citation statements)

References 39 publications

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“…Defects in airway barrier function may increase susceptibility to infection and inflammation, and underlie some aspects of disorders such as asthma and chronic obstructive pulmonary disease (5)(6)(7). There is also evidence that defects in the ability of basal cells to regenerate an intact epithelium after damage promote airway fibrosis (8).…”

mentioning

confidence: 99%

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Gao

Vockley

Pauli

et al. 2013

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

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Most of the airways of the human lung are lined by an epithelium made up of ciliated and secretory luminal cells and undifferentiated basal progenitor cells. The integrity of this epithelium and its ability to act as a selective barrier are critical for normal lung function. In other epithelia, there is evidence that transcription factors of the evolutionarily conserved grainyheadlike (GRHL) family play key roles in coordinating multiple cellular processes required for epithelial morphogenesis, differentiation, remodeling, and repair. However, only a few target genes have been identified, and little is known about GRHL function in the adult lung. Here we focus on the role of GRHL2 in primary human bronchial epithelial cells, both as undifferentiated progenitors and as they differentiate in air–liquid interface culture into an organized mucociliary epithelium with transepithelial resistance. Using a dominant-negative protein or shRNA to inhibit GRHL2, we follow changes in epithelial phenotype and gene transcription using RNA sequencing or microarray analysis. We identify several hundreds of genes that are directly or indirectly regulated by GRHL2 in both undifferentiated cells and air–liquid interface cultures. Using ChIP sequencing to map sites of GRHL2 binding in the basal cells, we identify 7,687 potential primary targets and confirm that GRHL2 binding is strongly enriched near GRHL2-regulated genes. Taken together, the results support the hypothesis that GRHL2 plays a key role in regulating many physiological functions of human airway epithelium, including those involving cell morphogenesis, adhesion, and motility.

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mentioning

confidence: 99%

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Gao

Vockley

Pauli

et al. 2013

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

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“…Epithelial cell-to-cell contacts, however, may become compromised in the airways of subjects with asthma, allowing epithelial cell mediators to reach the underlying structural cells. Several studies show that many adhesion proteins necessary for epithelial cell-to-cell contacts are downregulated in the airway epithelium of patients with asthma (131)(132)(133). Because of this uncertainty, determining the circumstances under which airway epithelium and subepithelium modify HASM contraction and relaxation responses will be essential for future studies investigating the effect of the surrounding milieu on HASM contraction and AHR.…”

Section: Contraction Cell Shortening and Cytoskeletal Motorsmentioning

confidence: 99%

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Ojiaku

Yoo

Panettieri

2017

Am J Respir Cell Mol Biol

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The pathogenesis of asthma includes a complex interplay among airway inflammation, hyperresponsiveness, and remodeling. Current evidence suggests that airway structural cells, including bronchial smooth muscle cells, myofibroblasts, fibroblasts, and epithelial cells, mediate all three aspects of asthma pathogenesis. Although studies show a connection between airway remodeling and changes in bronchomotor tone, the relationship between the two remains unclear. Transforming growth factor b1 (TGF-b1), a growth factor elevated in the airway of patients with asthma, plays a role in airway remodeling and in the shortening of various airway structural cells. However, the role of TGF-b1 in mediating airway hyperresponsiveness remains unclear. In this review, we summarize the literature addressing the role of TGF-b1 in airway remodeling and shortening. Through our review, we aim to further elucidate the role of TGF-b1 in asthma pathogenesis and the link between airway remodeling and airway hyperresponsiveness in asthma and to define TGF-b1 as a potential therapeutic target for reducing asthma morbidity and mortality.

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“…Asthma is commonly viewed as a disease dominated by enhanced adaptive immune responses leading to eosinophilic inflammation, but recent evidence indicates that innate immune responses originating from the respiratory epithelium contribute importantly to enhanced inflammation as well as mucous metaplasia and airway remodeling, which are important hallmarks of allergic asthma (3,4). Moreover, genetic or epigenetic alterations contribute to an altered respiratory epithelium, which is hyperreactive to allergen challenges and thereby mediates exaggerated responses to allergens during exacerbations (3,5).…”

Section: Introductionmentioning

confidence: 99%

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

Habibovic¹,

Hristova²,

Heppner³

et al. 2016

JCI Insight

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Defective epithelial barrier function in asthma

Cited by 503 publications

References 39 publications

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

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