Trek1 contributes to maintaining nasal epithelial barrier integrity

Jiang, Jie; Liu, Jiang‐Qi; Li, Jing; Li, Meng; Chen, Hongbin; Yan, Hao; Mo, Li‐Hua; Qiu, Shuqi; Liu, Zhigang; Yang, Ping‐Chang

doi:10.1038/srep09191

Cited by 33 publications

(38 citation statements)

References 37 publications

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“…There is accumulating evidence in human AR subjects and in animal models that IL‐4 has a role in nasal barrier dysfunction associated with changes in intercellular tight junction protein expression and the potassium channel protein, TREK‐1 . Moreover, the dysfunctional epithelial barrier in AR in clinical and experimental scenarios has been suggested to permit large molecules (e.g., FITC‐dextran MW of 4 kDa) to permeate into the sub‐mucosa . Based on this evidence, it is plausible that PPS may permeate across the disrupted epithelial layer in AR and thus enter the submucosal layer where it can interact with extracellular cytokines.…”

Section: Discussionmentioning

confidence: 99%

Broad Th2 neutralization and anti‐inflammatory action of pentosan polysulfate sodium in experimental allergic rhinitis

Sandén

Mori

Jogdand

et al. 2017

Immunity Inflam & Disease

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BackgroundTh2 cytokines like interleukin‐4, ‐5, and ‐13 are regarded as important drivers of the immunopathology underlying allergic rhinitis (AR) and asthma. The present study explores the capacity of pentosan polysulfate sodium (PPS), a semi‐synthetic heparin‐like macromolecular carbohydrate, to bind Th2 cytokines and exert biological neutralization in vitro, as well as anti‐inflammatory actions in vivo.MethodologyThe capacity of PPS to bind recombinant Th2 cytokines was tested with surface plasmon resonance (SPR) technology and biological Th2 neutralization was assessed by Th2‐dependent proliferation assays. The in vivo anti‐inflammatory action of PPS was studied using a validated Guinea‐pig model of AR.ResultsBinding studies revealed a strong and specific binding of PPS to IL‐4, IL‐5, and IL‐13 with IC values suggesting as stronger cytokine binding than for heparin. Cytokine binding translated to a biological neutralization as PPS dose dependently inhibited Th2‐dependent cell proliferation. Topical administration of PPS 30 min prior to nasal allergen challenge of sensitized animals significantly reduced late phase plasma extravasation, luminal influx of eosinophils, neutrophils, and total lavage leukocytes. Similar, albeit not statistically secured, effects were found for tissue leukocytes and mucus hyper‐secretion. The anti‐inflammatory effects of PPS compared favorably with established topical nasal steroid treatment.ConclusionThis study points out PPS as a potent Th2 cytokine‐binding molecule with biological neutralization capacity and broad anti‐inflammatory effects in vivo. As such PPS fulfills the role as a potential candidate molecule for the treatment of AR and further studies of clinical efficacy seems highly warranted.

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Section: Discussionmentioning

confidence: 99%

Broad Th2 neutralization and anti‐inflammatory action of pentosan polysulfate sodium in experimental allergic rhinitis

Sandén

Mori

Jogdand

et al. 2017

Immunity Inflam & Disease

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“…The TWIK-related potassium channel-1 (TREK-1) is the most extensively studied 2-pore domain K 1 channel expressed in the central nervous system, small intestine, and kidney. [6][7][8] Although TREK-1 acts as an important regulator of the cell membrane potential, recent reports revealed that the expression levels of TREK-1 were significantly lower in patients with allergic rhinitis and in rats with ovalbumin experimentally induced nasal allergy. In addition, it has been shown that TREK-1 participates in epithelial barrier function in a mouse model of intestinal allergy.…”

Section: Role Of Twik-related Potassium Channel-1 In Chronic Rhinosinmentioning

confidence: 99%

“…In addition, it has been shown that TREK-1 participates in epithelial barrier function in a mouse model of intestinal allergy. 7,9 Moreover, TREK-1 contributes to the maintenance of endothelial barrier integrity in the blood-brain barrier and regulates vasodilation in mesenteric resistance arteries and in skin microvessels. E1-E3 In this respect, we hypothesized that TREK-1 plays a crucial role in the maintenance of the epithelial and endothelial barrier in human sinonasal mucosa.…”

Section: Role Of Twik-related Potassium Channel-1 In Chronic Rhinosinmentioning

confidence: 99%

Role of TWIK-related potassium channel-1 in chronic rhinosinusitis

Kim

et al. 2018

Journal of Allergy and Clinical Immunology

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All 3 SKIs, BIRB796, dasatinib, and R343, as well as the combinations BIRB796/dasatinib and dasatinib/R343 did not significantly inhibit LPS-induced CXCL8 in non-COPD HASMCs. In contrast, the BIRB796/R343 double combination and the BIRB796/dasatinib/R343 triple combination both showed strong inhibitory effects (see Fig E4, A and B, in this article's Online Repository at www.jacionline.org). This suggests dominant roles for p38MAPK and Syk but not for Src in the regulation of LPS-induced CXCL8. As the BIRB796/dasatinib combined treatment, the NSKI RV568 did not significantly inhibit LPS-induced CXCL8. In contrast, RV1088 potently suppressed CXCL8 in LPS-exposed HASMCs and was almost equally effective as the BIRB796/R343 double and the BIRB796/dasatinib/R343 triple combination. RV1088 was superior to any SKI in single treatments (Fig E4, A and B). In COPD HASMCs, RV1088 almost completely inhibited LPS-induced CXCL8. RV1088 was superior to RV568, to BIRB796, and to FP, all of which only showed weak inhibitory effects (Fig 1, E and F; Table I). Dasatinib and R343 in single treatments and the dasatinib/ R343 combination did not inhibit LPS-induced GM-CSF in non-COPD HASMCs. BIRB796 single treatment as well as the BIRB796/R343 and BIRB796/dasatinib combinations all partially suppressed LPS-induced GM-CSF, and BIRB796/ dasatinib was most effective. The BIRB796/dasatinib/R343 triple combination was superior to any double combination (see Fig E5, A and B, in this article's Online Repository at www.jacionline. org). This suggests that p38MAPK-, Src-, and Syk-family kinases are involved in the regulation of LPS-induced GM-CSF. RV568 and RV1088 were equally effective as the BIRB796/dasatinib double or BIRB796/dasatinib/R343 triple combination, respectively. RV1088 was superior to RV568 and to any single and double treatment (Fig E5, A and B). In COPD HASMCs, RV1088 completely inhibited LPS-induced GM-CSF. RV1088 was superior to RV568 and to BIRB796, both of which showed partial inhibitory effects (Fig 1, G and H; Table I). RV1088 was by trend also superior to the strong effects of FP. Data in the Online Repository (see Figs E6 and E7 in this article's Online Repository at www.jacionline.org) suggest (1) that differential sensitivities of CXCL8 and GM-CSF for NSKIs in different models depend on transcriptional regulation and (2) that NSKIs affect posttranscriptional CXCL8 regulation in the TNF-a but not in the LPS model. Our data provide strong evidence for a utility of a new anti-inflammatory therapeutic strategy in COPD: NSKIs suppress corticosteroid-sensitive and corticosteroid-insensitive cytokine production in in vitro models of COPD and they are superior to sole p38MAPK inhibition and to SKIs that target Src and Syk. Targeting p38MAPK, Src, and Syk may be more effective than targeting only 2 of these 3 kinases (details are discussed in this article's Online Repository at www.jacionline.org). The limitation of this study is a lack of kinase-specific approaches using siRNA or knockout experiments. We cannot exclude off-ta...

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“…Two subunits of these channels form functional channels (12). Although its original function was considered to be for K + ion transportation, recent reports have revealed that TREK-1 is implicated in the maintenance of epithelial and endothelial barrier integrity (10,13). Huang et al (10) reported that TREK-1 deficiency induced barrier dysfunction in a human colon epithelial cell line and their data strongly suggested that TREK-1 is required for the maintenance of intestinal epithelial barrier integrity.…”

Section: Trek-1 In Hirschsprung's Diseasementioning

confidence: 99%

“…The proinflammatory environment associated with the secretion of these mediators promotes neutrophil-, macrophage-, T-cell, and epithelium-mediated injury resulting in loss of barrier function. Furthermore, Jiang et al (13) reported, that nasal epithelia express TREK-1; and that the suppression of TREK-1 with IL-4 via an upregulated expression of histone deacetylase leads to nasal epithelial dysfunction. All the above studies suggest a major role of TREK-1 in the maintenance of the epithelial barrier function in different tissues.…”

Section: Trek-1 In Hirschsprung's Diseasementioning

confidence: 99%