TNF-α–mediated bronchial barrier disruption and regulation by src-family kinase activation

Hardyman, Michelle A; Wilkinson, Emily; Ernst, Martin; Jayasekera, Nivenka; Blume, Cornelia; Swindle, Emily J.; Gozzard, Neil; Holgate, Stephen T.; Howarth, Peter H.; Davies, Donna E.; Collins, Jane

doi:10.1016/j.jaci.2013.03.005

Cited by 100 publications

(88 citation statements)

References 63 publications

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“…Src family kinases play a key role in sensitizing airway smooth muscle and may play a role in AHR via activation of ROCK and is reversed by the Src inhibitor PP2 (Shaifta et al, 2015). TNF-a disrupts airway epithelial barrier function and this is mediated via Src activation and prevented by a Src inhibitor SU6656 [2,3-dihydro-N,N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide] (Hardyman et al, 2013). The Src inhibitor PP2 and siRNA knockdown of Src prevents rhinovirusinduced release of CXCL8 from human airway epithelial cells (Bentley et al, 2007).…”

Section: Src Family Kinase Inhibitionmentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

100

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Section: Src Family Kinase Inhibitionmentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

100

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“…is preserved. Moreover, the epithelia respond in a regulated and vectorial manner to the pro-inflammatory stimulus TNF-α (Hardyman et al, 2013). A large panel of cytokines, chemokines and metalloproteinases has been detected (e.g., IL-8, IL-6, GM-CSF, MMP-9, GRO-α, etc.).…”

Section: Primary Lung Cellsmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

122

103

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SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

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Section: Discussionmentioning

confidence: 99%

“…In turn, the epithelial barrier function is compromised in different tissues, including the brain and lungs (6,23). Subsequently, a decrease in transepithelial electrical resistance occurs, and increased epithelial permeability in asthmatic air-liquid interface cultures has been observed (23). TNF-α is not only effective on bronchial epithelial TJs, but also on other tissues, including retinal epithelial cells, where the cytokine increases the levels of matrix metalloproteinases, which in turn degrade claudin-1 and occludin, increasing permeability (24).…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor antagonism restores epithelial barrier dysfunction via affecting zonula occludens proteins

Yüksel

Yılmaz

Karaman

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Epithelial barrier dysfunction is important in the pathogenesis of asthma and allergic responses, and is therefore a therapeutic target. The aim of the present study was to investigate the effects of dexamethasone, a classic therapeutic agent, an anti-tumor necrosis factor agent (etanercept), which is used to treat difficult cases of asthma, and an anti-vascular endothelial growth factor (VEGF) agent (bevacizumab), which is an angiogenesis inhibitor, on zonula occludens (ZO) proteins in an experimental asthma model. The experimental model of asthma was developed using intraperitoneal (IP) and inhaled administration of ovalbumin in 38 BALB/c mice, which were divided into four groups. The control group (n=6) did not receive any treatment, while the four remaining groups (n=8 per group) received an IP injection of saline, etanercept, bevacizumab or dexamethasone, respectively. Occludin, claudin and junctional adhesion molecule (JAM) were immunohistochemically stained in the left middle lobe samples using an indirect avidin-peroxidase method, after which the staining was semiquantified with H-scores. Statistically significant differences were observed in the occludin, claudin and JAM H-scores among the four groups (P<0.001). In the untreated asthma, etanercept, bevacizumab and dexamethasone groups, the median H-scores for occludin were 93, 177, 280 and 198, respectively, while the H-scores for claudin were 82, 193.5, 274 and 202.5, respectively, and the median H-scores for JAM were 130, 210, 288 and 210, respectively. Pairwise comparisons revealed that all three ZO protein H-scores were significantly lower in the saline group when compared with each treatment group. However, the H-scores of the ZO proteins were not significantly different between the etanercept and dexamethasone groups. Furthermore, the bevacizumab group exhibited higher H-scores for all the proteins compared with the dexamethasone group. Therefore, antagonism of VEGF with bevacizumab restores the epithelial barrier to a greater extent when compared with dexamethasone treatment. This result may be promising for the development of novel therapeutic agents. IntroductionEpithelial tissue, in addition to forming a physical barrier to external stimuli, plays a major role in the regulation of the adaptive immune response. The physical barrier function of the epithelium is attained via cell-cell interactions and via impermeable tight junctions (TJs) that are located subapically (1).Claudins, occludin and junctional adhesion molecules (JAMs) are major constituent proteins of TJs. The claudin family comprises 24 members, and determines the TJ charge selectivity and the location of the paracellular space (2). In addition, human fetal lung cells have been shown to use differential claudin expression to regulate TJ permeability (3). Occludin is an additional protein that is important in barrier formation and regulation (2). JAM-1, which is a member of the immunoglobulin superfamily, has been shown to interact with zonula occludens (ZO)-1, occludin and...

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TNF-α–mediated bronchial barrier disruption and regulation by src-family kinase activation

Abstract: Inhibiting TNF-α or src kinases may be a therapeutic option to normalize barrier integrity and cytokine release in airway diseases associated with barrier dysfunction.

Cited by 100 publications

References 63 publications

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Vascular endothelial growth factor antagonism restores epithelial barrier dysfunction via affecting zonula occludens proteins

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