Inhibition of Pendrin by a small molecule reduces Lipopolysaccharide-induced acute Lung Injury

Lee, Eun Hye; Shin, Mi Hwa; Gi, Mia; Park, Jin‐Hong; Song, Doona; Hyun, Young-Min; Ryu, Ji Hwan; Seong, Je Kyung; Jeon, Yoon Kyung; Han, Gyoonhee; Namkung, W.; Park, Moo Suk; Choi, Jae Young

doi:10.7150/thno.46417

Cited by 32 publications

(23 citation statements)

References 31 publications

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“…Our study demonstrated that LPS significantly upregulated the expression of TLR4, p-IKKα/β, p-IκBα, and p-NF-κB but decreased expression of IKKα/β, IκBα, and NF-κB. Other studies reported that LPS induced overexpression of NF-κB or kept constant ( Lee et al, 2020 ; Li et al, 2020 ; Zhang et al, 2020 ). To solve this inconsistent question, we tested different dosages and different stimulus times of LPS on NF-κB expression and found that the NF-κB expression was upregulated by LPS on 1 mg/kg at 4 h, 5 mg/kg at both 2 and 4 h, and 10 mg/ kg at 2 h. Meanwhile, the LPS on 2 mg/ kg at 2 h and 10 mg/ kg at 4 h significantly decreased the NF-κB expression ( Supplementary Figure S1 ).…”

Section: Discussionsupporting

confidence: 59%

Qingwenzhike Prescription Alleviates Acute Lung Injury Induced by LPS via Inhibiting TLR4/NF-kB Pathway and NLRP3 Inflammasome Activation

Zhang

Wang

et al. 2021

Front. Pharmacol.

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Background: Acute lung injury (ALI) is characterized by dysfunction of the alveolar epithelial membrane caused by acute inflammation and tissue injury. Qingwenzhike (QWZK) prescription has been demonstrated to be effective against respiratory viral infections in clinical practices, including coronavirus disease 2019 (COVID-19) infection. So far, the chemical compositions, protective effects on ALI, and possible anti-inflammatory mechanisms remain unknown.Methods: In this study, the compositions of QWZK were determined via the linear ion trap/electrostatic field orbital trap tandem high-resolution mass spectrometry (UHPLC-LTQ-Orbitrap MS). To test the protective effects of QWZK on ALI, an ALI model induced by lipopolysaccharide (LPS) in rats was used. The effects of QWZK on the LPS-induced ALI were evaluated by pathological changes and the number and classification of white blood cell (WBC) in bronchoalveolar lavage fluid (BALF). To investigate the possible underlying mechanisms, the contents of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP-1), interleukin-1β (IL-1β), interleukin-18 (IL-18), and immunoregulatory-related factors interferon-γ (IFN-γ) were detected by ELISA. Furthermore, the expression of Toll-like receptor 4 (TLR4), p-IKKα/β, IKKα, IKKβ, p-IκBα, IκBα, p-NF-κB, nuclear factor-κB (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, pro-caspase-1, apoptosis-associated speck-like protein containing CARD (ASC), and β-actin were tested by Western blot.Results: A total of 99 compounds were identified in QWZK, including 33 flavonoids, 23 phenolic acids, 3 alkaloids, 3 coumarins, 20 triterpenoids, 5 anthraquinones, and 12 others. ALI rats induced by LPS exhibited significant increase in neutrophile, significant decrease in lymphocyte, and evidently thicker alveolar wall than control animals. QWZK reversed the changes in WBC count and alveolar wall to normal level on the model of ALI induced by LPS. ELISA results revealed that QWZK significantly reduced the overexpression of proinflammatory factors IL-6, TNF-α, MCP-1, IL-1β, IL-18, and IFN-γ induced by LPS. Western blot results demonstrated that QWZK significantly downregulated the overexpression of TLR4, p-IKKα/β, p-IκBα, p-NF-κB, NLRP3, cleaved caspase-1, and ASC induced by LPS, which suggested that QWZK inhibited TLR4/NF-κB signaling pathway and NLRP3 inflammasomes.Conclusions: The chemical compositions of QWZK were first identified. It was demonstrated that QWZK showed protective effects on ALI induced by LPS. The possible underlying mechanisms of QWZK on ALI induced by LPS was via inhibiting TLR4/NF-kB signaling pathway and NLRP3 inflammasome activation. This work suggested that QWZK is a potential therapeutic candidate for the treatments of ALI and pulmonary inflammation.

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Section: Discussionsupporting

confidence: 59%

Qingwenzhike Prescription Alleviates Acute Lung Injury Induced by LPS via Inhibiting TLR4/NF-kB Pathway and NLRP3 Inflammasome Activation

Zhang

Wang

et al. 2021

Front. Pharmacol.

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“…Furthermore, a significantly negative correlation was observed for serum levels of SLC26A4 and FEV 1 when analyses were performed for serum levels of SLC26A4 and pulmonary function parameters among asthmatic patients. These findings were consistent with a recent report that SLC26A4 was elevated in human BALF of patients with acute respiratory distress syndrome (ARDS) compared with the control subjects ( 69 ). However, the exact function of the soluble form of SLC26A4 in airway inflammation has been well studied for SLC26A4 as a membrane-associated anion transporter, but it remains unknown; this would be of interest to pursue in the future.…”

Section: Discussionsupporting

confidence: 93%

Type II alveolar epithelial cell–specific loss of RhoA exacerbates allergic airway inflammation through SLC26A4

Danh¹,

Zhang²,

Tu³

et al. 2021

JCI Insight

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The small GTPase RhoA and its downstream effectors are critical regulators in the pathophysiological processes of asthma. The underlying mechanism, however, remains undetermined. Here, we generated asthma mouse model with RhoA conditional knockout mice (Sftpc-cre;RhoA f/f ) in type II alveolar epithelial cells (AT2) and demonstrated that AT2 cell specific deletion of RhoA leads to exacerbation of allergen-induced airway hyper-responsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, Sftpccre;RhoA f/f mice showed a significant reduction in Tgf-β1 levels in BALFs and lung tissues, and administration of recombinant Tgf-β1 to the mice rescued Tgf-β1 and alleviated the increased allergic airway inflammation observed in Sftpc-cre;RhoA f/f mice. Using RNA-seq technology, we identified Slc26a4 (pendrin), a transmembrane anion exchange, as the most up-regulated gene in RhoA-deficient AT2 cells. The up-regulation of SLC26A4 was further confirmed in AT2 cells of asthmatic patients and mouse model and in human airway epithelial cells expressing dominantnegative RHOA (RHOA-N19). SLA26A4 was also elevated in serum from asthmatic patients and negatively associated with FEV1%. Furthermore, SLC26A4 inhibition promoted epithelial TGF-β1 release and attenuated allergic airway inflammation. Our study reveals a previously undefined RhoA-SLC26A4 axis in AT2 cells that functions as a protective mechanism against allergic airway inflammation.Teaser: RhoA in type II alveolar epithelial cells controls allergic airway inflammation through anion exchange SLC26A4 in asthma

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“…Hematoxylin and eosin (HE) staining was performed by following the method routinely used in our laboratory [29]. The images were acquired using a Leica microscope (Leica Microsystems, Germany), and the lung injury score was assessed by five easily identifiable pathological processes according to the official ATS workshop report [30,31].…”

Section: Knock-in and Knockdown Of Sirt3mentioning

confidence: 99%

Sirt3 Maintains Microvascular Endothelial Adherens Junction Integrity to Alleviate Sepsis‐Induced Lung Inflammation by Modulating the Interaction of VE‐Cadherin and β‐Catenin

Chen

Shen

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Inflammatory injury is a hallmark of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). However, the mechanisms underlying inflammatory injury remain obscure. Here, we developed the novel strategy to suppress lung inflammation through maintaining microvascular endothelial barrier integrity. VE-cadherin is the main adherens junction protein that interacts with β-catenin and forms a complex. We found that lung inflammation was accompanied by decreased VE-cadherin expression and increased β-catenin activity in animal models and human pulmonary microvascular endothelial cells (HPMECs), illuminating the relationship among VE-cadherin/β-catenin complex, microvascular endothelial barrier integrity, and inflammation. Furthermore, we showed that the VE-cadherin/β-catenin complex dissociated upon lung inflammation, while Sirt3 promoted the stability of such a complex. Sirt3 was decreased during lung inflammation in vivo and in vitro. Sirt3 deficiency not only led to the downregulation of VE-cadherin but also enhanced the transcriptional activity of β-catenin that further increased β-catenin target gene MMP-7 expression, thereby promoting inflammatory factor COX-2 expression. Sirt3 overexpression promoted VE-cadherin expression, inhibited β-catenin transcriptional activity, strengthened the stability of the VE-cadherin/β-catenin complex, and suppressed inflammation in HPMECs. Notably, Sirt3 deficiency significantly damaged microvascular endothelial barrier integrity and intensified lung inflammation in animal model. These results demonstrated the role of Sirt3 in modulating microvascular endothelial barrier integrity to inhibit inflammation. Therefore, strategies that aim at enhancing the stability of endothelial VE-cadherin/β-catenin complex are potentially beneficial for preventing sepsis-induced lung inflammation.

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Inhibition of Pendrin by a small molecule reduces Lipopolysaccharide-induced acute Lung Injury

Cited by 32 publications

References 31 publications

Qingwenzhike Prescription Alleviates Acute Lung Injury Induced by LPS via Inhibiting TLR4/NF-kB Pathway and NLRP3 Inflammasome Activation

Qingwenzhike Prescription Alleviates Acute Lung Injury Induced by LPS via Inhibiting TLR4/NF-kB Pathway and NLRP3 Inflammasome Activation

Type II alveolar epithelial cell–specific loss of RhoA exacerbates allergic airway inflammation through SLC26A4

Sirt3 Maintains Microvascular Endothelial Adherens Junction Integrity to Alleviate Sepsis‐Induced Lung Inflammation by Modulating the Interaction of VE‐Cadherin and β‐Catenin

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