Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells

Schwingshackl, Andreas; Teng, Bo; Ghosh, Manik C.; Lim, Keng Gat; Tigyi, Gábor; Narayanan, Damodaran; Jaggar, Jonathan H.; Waters, Christopher M.

doi:10.1152/ajplung.00299.2012

Cited by 31 publications

(44 citation statements)

References 60 publications

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“…The weak cytokine response to HO exposure is similar to our in vitro findings in alveolar epithelial cells, where HO alone did not induce significant IL-6, MCP-1 or RANTES release[18]. Consistent with our previous in vitro findings in Trek-1 deficient AECs[17], injury caused by HO+MV resulted in decreased IL-6 levels in the BAL fluid of Trek-1 deficient mice. However, MCP-1 levels were also decreased in the BAL fluid of Trek-1 deficient mice, whereas in vi tro MCP-1 secretion was increased from Trek-1 deficient AECs[31].…”

Section: Discussionsupporting

confidence: 91%

“…We previously proposed a role for TREK-1 in cytokine secretion from alveolar epithelial cells[17, 18] and now investigated whether TREK-1 also plays a role in an in vivo model of hyperoxia (HO)-induced lung injury. We exposed WT and TREK-1 deficient mice to either 24 hours of HO alone, or 24 hours of HO followed by 4 hours of injurious mechanical ventilation (MV) and analyzed lung morphology (Figure 1A), lung histology (Figure 1B), and a 5-point composite lung injury score (LIS) from each section (Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported the expression of K2P channels in alveolar epithelial cells (AECs) and found that TNF-α stimulation of TREK-1 deficient AECs caused decreased IL-6 secretion but increased MCP-1 secretion in vitro [17, 18]. Therefore, we were interested in determining whether in vivo TREK-1 deficiency would ultimately promote a pro- or anti-inflammatory phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…We previously suggested that the K2P channel TREK-1 may play a regulatory role in the development of alveolar epithelial injury. We found that TREK-1 deficiency altered the cytokine release profile of alveolar epithelial cells upon TNF-α stimulation, resulting in decreased IL-6 and increased MCP-1 secretion[17, 18]. Although activation of several TNF-α induced signaling pathways, including p38 kinase and the PKCθ isoform, appeared altered in TREK-1 deficient epithelial cells, the specific regulatory mechanisms underlying these signaling changes remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Schwingshackl

Teng

Makena

et al. 2014

Critical Care Medicine

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Objective We previously reported the expression of the 2-pore domain K+ channel TREK-1 in lung epithelial cells and proposed a role for this channel in the regulation of alveolar epithelial cytokine secretion. In this study we focused on investigating the role of TREK-1 in vivo in the development of hyperoxia-induced lung injury. Design Laboratory animal experiments. Setting University research laboratory. Subjects Wild type and TREK-1 deficient mice. Interventions Mice were anesthetized and exposed to 1) room air, no mechanical ventilation, 2) 95% hyperoxia for 24 hours, 3) 95% hyperoxia for 24 hours followed by mechanical ventilation for 4 hours. Measurements and Main Results Hyperoxia exposure accentuated lung injury in TREK-1 deficient mice but not controls, resulting in increased in Lung Injury Scores (LIS), broncho-alveolar lavage (BAL) fluid cell numbers and cellular apoptosis, and a decrease in quasi-static lung compliance. Exposure to a combination of hyperoxia and injurious mechanical ventilation resulted in further morphological lung damage, increased LIS and BAL fluid cell numbers in control but not TREK-1 deficient mice. At baseline and after hyperoxia exposure BAL cytokine levels were unchanged in TREK-1 deficient mice compared to controls. Exposure to hyperoxia and mechanical ventilation resulted in an increase in BAL IL-6, MCP-1 and TNF-α levels in both mouse types, but the increase in IL-6 and MCP-1 levels was less prominent in TREK-1 deficient mice than in controls. Lung tissue MIP-2, KC and IL-1β gene expression was not altered by hyperoxia in TREK-1 deficient mice compared to controls. Furthermore, we show for the first time TREK-1 expression on alveolar macrophages and unimpaired TNF-α secretion from TREK-1 deficient macrophages. Conclusion TREK-1 deficiency resulted in increased sensitivity of lungs to hyperoxia but this effect is less prominent if overwhelming injury is induced by the combination of hyperoxia and injurious mechanical ventilation. TREK-1 may constitute a new potential target for the development of novel treatment strategies against hyperoxia-induced lung injury.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Schwingshackl

Teng

Makena

et al. 2014

Critical Care Medicine

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“…In this study, the signaling pathway NF-κB was found to be involved in the antiinflammatory action of baicalin. A range of adaptor molecules binded to TLR (e.g., LPS and TNF-α) could activate the NF-κB signaling pathway [20][21][22][23]. Activation occurs via phosphorylation of IκB at Ser32 and Ser36 by LPS, resulting in the ubiquitin-mediated proteasome-dependent degradation of IκBα and the release and nuclear translocation of active NF-κB dimers.…”

Section: Discussionmentioning

confidence: 99%

Baicalin Inhibits Lipopolysaccharide-Induced Inflammation Through Signaling NF-κB Pathway in HBE16 Airway Epithelial Cells

Dong

Zhong

Lu³

et al. 2015

Inflammation

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Baicalin, a flavonoid monomer derived from Scutellaria baicalensis called Huangqin in mandarin, is the main active ingredient contributing to S. baicalensis' efficacy. It is known in China that baicalin has potential therapeutic effects on inflammatory diseases. However, its anti-inflammatory mechanism has still not been fully interpreted. We aim to investigate the anti-inflammatory effect of baicalin on lipopolysaccharide (LPS)-induced inflammation in HBE16 airway epithelial cells and also to explore the underlying signaling mechanisms. The anti-inflammatory action of baicalin was evaluated in human airway epithelial cells HBE16 treated with LPS. Airway epithelial cells HBE16 were pretreated with a range of concentrations of baicalin for 30 min and then stimulated with 10 μg/ml LPS. The secretions of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) in cell culture supernatants were quantified by enzyme-linked immunosorbent assay (ELISA). The messenger RNA (mRNA) expressions of IL-6, IL-8, and TNF-α were tested by quantitative real-time polymerase chain reaction (real-time RT-PCR). Furthermore, Western blotting was used to determine whether the signaling pathway NF-κB was involved in the anti-inflammatory action of baicalin. The inflammatory cell model was successfully built with 10 μg/ml LPS for 24 h in our in vitro experiments. Both the secretions and the mRNA expressions of IL-6, IL-8, and TNF-α were significantly inhibited by baicalin. Moreover, the expression levels of phospho-IKKα/β and phospho-NF-κB p65 were downregulated, and the phospho-IκB-α level was upregulated by baicalin. These findings suggest that the anti-inflammatory properties of baicalin may be resulted from the inhibition of IL-6, IL-8, and TNF-α expression via preventing signaling NF-κB pathway in HBE16 airway epithelial cells. In addition, this study provides evidence to understand the therapeutic effects of baicalin on inflammatory diseases in clinical practice.

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Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial

et al. 2016

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Objective A double-blind, randomized controlled trial showed that low-dose glucocorticoid therapy in pediatric ARDS patients is feasible and may improve both ventilation and oxygenation indices in these patients. However, the molecular mechanisms underlying potential changes in outcomes remain unclear. Based on these clinical findings, this study was designed to examine the effects of intravenous methylprednisolone on circulating inflammatory biomarkers in pediatric ARDS patients. Design Double-blind, placebo-controlled randomized trial with blood collection on study entry and day 7. Setting Tertiary care children’s hospital. Patients Children (0–18 years) with ARDS undergoing mechanical ventilation. Interventions 35 children were randomized within 72 hours of mechanical ventilation. The glucocorticoid group received methylprednisolone 2 mg/kg loading dose followed by 1 mg/kg/day continuous infusion from days 1–7. Both groups were ventilated following the ARDSnet recommendations. WBC and differential cell counts, plasma cytokines and CRP levels, and coagulation parameters were analyzed on days 0 and 7. Results At study entry, the placebo group had higher IL-15 and basophil levels. On day 7, in comparison to study entry, the placebo group had lower IL-1α, IFN-γ and IL-10 levels. The glucocorticoid group had lower INF-α, IL-6, IL-10, MCP-1, G-CSF and GM-CSF levels, and higher IL-17α levels on day 7 in comparison to study entry. Total and differential cell counts remained unchanged within the placebo group between days 0 and 7, whereas in the glucocorticoid group total WBC and platelets counts were increased on day 7. Pearson’s correlation studies within the placebo and glucocorticoid groups revealed positive and negative correlations between cytokine levels, cell counts, coagulation parameters and relevant clinical parameters of disease severity identified in our previous study. Multiple regression models identified several cytokines as predictors for alterations in clinical parameters of disease severity. Conclusion This pilot study shows the feasibility of simultaneously measuring multiple inflammatory cytokines, cell counts and coagulation parameters in pediatric ARDS patients. We report statistical models that may be useful for future, larger trials to predict ARDS severity and outcomes.

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Regulation of interleukin-6 secretion by the two-pore-domain potassium channel Trek-1 in alveolar epithelial cells

Cited by 31 publications

References 60 publications

Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Baicalin Inhibits Lipopolysaccharide-Induced Inflammation Through Signaling NF-κB Pathway in HBE16 Airway Epithelial Cells

Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial

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