SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury

AbstractSARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.

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SARS-CoV-2-Triggered Mast Cell Rapid Degranulation Induces Alveolar Epithelial Inflammation and Lung Injury

10.1101/2021.06.24.449680 ◽

2021 ◽

Author(s):

Meng-Li Wu ◽

Feng-Liang Liu ◽

Jing Sun ◽

Xin Li ◽

Xiao-Yan He ◽

...

Keyword(s):

Lung Injury ◽

Lung Inflammation ◽

Rhesus Macaques ◽

Alveolar Epithelial Cells ◽

Humanized Mice ◽

Inflammatory Factors ◽

Off Label Use ◽

Off Label ◽

Alveolar Epithelial ◽

Epithelial Inflammation

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. Here we showed that SARS-CoV-2-triggeed MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation alterred various signaling pathways in alveolar epithelial cells, particularly, led to the production of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.

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The MUC5B Mucin Is Involved in Paraquat-Induced Lung Inflammation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7028947 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Hao Sun ◽

Yunfei Jiang ◽

Yang Song ◽

Xiaomin Zhang ◽

Jun Wang ◽

...

Keyword(s):

Lung Inflammation ◽

Culture Medium ◽

Mapk Pathway ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Inflammatory Factors ◽

Enzyme Linked Immunosorbent Assay ◽

Dot Blot ◽

Alveolar Epithelial ◽

Dose Dependent

Objective. Paraquat (PQ), a widely used toxic herbicide, induces lung inflammation through mechanisms that remain incompletely understood. In a previous study, we found that the plasma MUC5B mucin level was implicated in PQ poisoning in patients. Here, we hypothesize that MUC5B is a critical mediator in PQ-induced cell inflammation. Methods. A mouse model of PQ-induced lung injury was used to examine the MUC5B expression level. A549 cells (alveolar epithelial cells line) were exposed to PQ in dose-dependent and time-dependent manners. Cell viability was detected by CCK-8 assays. The expression levels of MUC5B were examined by dot blot enzyme-linked immunosorbent assay (ELISA) and RT-qPCR. Western blotting was used to detect the levels of proteins in the MAPK and NF-κB pathways. Inflammatory factors in the cell culture medium were measured by ELISA. NF-κB and MAPK pathway inhibitors and MUC5B siRNA (siMUC5B) were used to determine the function of MUC5B. Finally, N-acetyl-cysteine (NAC) was added and its regulatory effect on the MAPK-NF-κB-MUC5B pathway was examined in PQ-induced cell inflammation. Results. MUC5B was significantly upregulated accompanying the increases in TNF-α and IL-6 secretion following PQ treatment in mouse and also in A549 cells after treatment with 50 μM PQ at 24 hours. Furthermore, MAPK and NF-κB pathway inhibitors could dramatically decrease the expression of MUC5B and the secretion of TNF-α and IL-6. Importantly, siMUC5B could significantly attenuate the secretion of TNF-α and IL-6 induced by PQ. As expected, the addition of NAC efficiently suppresses the TNF-α and IL-6 secretion stimulated from PQ and also downregulated ERK, JNK, and p65 phosphorylation (ERK/JNK MAPK and NF-κB pathways) as well as MUC5B expression. Conclusion. Our findings suggest that MUC5B participates in the process of PQ-induced cell inflammation and is downstream of the NF-κB and MAPK pathways. NAC can attenuate PQ-induced cell inflammation at least in part by suppressing the MAPK-NF-κB-MUC5B pathway. These results nominate MUC5B as a new biomarker and therapeutic target for PQ-induced lung inflammation.

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Multiple Biological Roles of Extracellular Vesicles in Lung Injury and Inflammation Microenvironment

BioMed Research International ◽

10.1155/2020/5608382 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Gang Su ◽

Xiaohong Ma ◽

Haidong Wei

Keyword(s):

Lung Injury ◽

Viral Infection ◽

Extracellular Vesicles ◽

Immune Cells ◽

Lung Inflammation ◽

Pathological Process ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial ◽

Cell Sources

Lung injury and inflammation are complex pathological processes. The influence and crosstalk between various cells form a characteristic microenvironment. Extracellular vesicles from different cell sources in the microenvironment carry multiple cargo molecules, which affect the pathological process through different pathways. Here, we mainly discussed the mechanism of crosstalk between alveolar epithelial cells and different immune cells through extracellular vesicles in lung inflammation and reviewed the mechanism of extracellular vesicles released by blood and airways on lung inflammation. Finally, the role of extracellular vesicles in viral infection of the lung was also described.

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Lats2-Underexpressing Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate LPS-Induced Acute Lung Injury in Mice

Mediators of Inflammation ◽

10.1155/2019/4851431 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Liang Dong ◽

Lang Li

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Lung Inflammation ◽

Alveolar Epithelial Cells ◽

Lung Edema ◽

Alveolar Epithelial

The pathophysiology of the acute lung injury (ALI) is characterized by the damage of alveolar epithelial cells, which can be repaired by exogenous bone marrow-derived mesenchymal stem cells (BMSCs). However, the migration and differentiation abilities of BMSCs are not sufficient for the purpose, and a new approach that could strengthen the repair effects of BMSCs in ALI still needs to be clarified. We have previously proved that in vitro large tumor suppressor kinase 2- (Lats2-) underexpressing BMSCs may enhance their tissue repair effects in ALI; thus, in the present study, we tried to explore whether Lats2-underexpressing BMSCs could rescue lipopolysaccharide- (LPS-) induced ALI in vivo. BMSCs from C57BL/6 mice transfected with Lats2-interfering lentivirus vector or lentivirus blank controls were transplanted intratracheally into LPS-induced ALI mice. The retention and differentiation of BMSCs in the lung were evaluated by in vivo imaging, immunofluorescence staining, and Western blotting. The lung edema and permeability were assessed by lung wet weight/body weight ratio (LWW/BW) and measurements of proteins in bronchoalveolar lavage fluid (BALF) using ELISA. Acute lung inflammation was measured by the cytokines in the lung homogenate and BALF using RT-qPCR and ELISA, respectively. Lung injury was evaluated by HE staining and lung injury scoring. Pulmonary fibrosis was evaluated by Picrosirius red staining, immunohistochemistry for α-SMA and TGF-β1, and hydroxyproline assay and RT-qPCR for Col1α1 and Col3α1. Lats2-mediated inhibition of the Hippo pathway increased the retention of BMSCs and their differentiation toward type II alveolar epithelial cells in the lung. Furthermore, Lats2-underexpressing BMSCs improved lung edema, permeability of the lung epithelium, and lung inflammation. Finally, Lats2-underexpressing BMSCs alleviated lung injury and early pulmonary fibrosis. Our studies suggest that underexpression of Lats2 could further enhance the repair effects of BMSCs against epithelial impair and the therapeutic potential of BMSCs in ALI mice.

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Ghrelin ameliorates bleomycin-induced acute lung injury by protecting alveolar epithelial cells and suppressing lung inflammation

European Journal of Pharmacology ◽

10.1016/j.ejphar.2011.09.183 ◽

2011 ◽

Vol 672 (1-3) ◽

pp. 153-158 ◽

Cited By ~ 41

Author(s):

Yoshifumi Imazu ◽

Shigehisa Yanagi ◽

Kahori Miyoshi ◽

Hironobu Tsubouchi ◽

Shu-ichi Yamashita ◽

...

Keyword(s):

Acute Lung Injury ◽

Epithelial Cells ◽

Lung Injury ◽

Lung Inflammation ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial

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Tea Polyphenols Prevent Sepsis-Induced Lung Injury via Promoting Translocation of DJ-1 to Mitochondria

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.622507 ◽

2021 ◽

Vol 9 ◽

Author(s):

Chun-Mei Jia ◽

Feng-Wei Zhang ◽

Shu-Juan Wang ◽

Wei Wang ◽

Yong Li

Keyword(s):

Lung Injury ◽

Cecal Ligation ◽

Normal Function ◽

Alveolar Epithelial Cells ◽

Tea Polyphenols ◽

Inflammatory Factors ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Alveolar Epithelial

BackgroundSepsis is the systemic inflammatory response syndrome caused by infection, which commonly targets on the lung. Tea polyphenols (TP) have many pharmacological activities, but their role in sepsis induced lung injury remains unclear.ResultsInjection of TP after cecal ligation and puncture (CLP) operation elevated the survival rate in a concentration dependent manner. TP treatment improved alveoli structure injury under CLP operation. CLP surgery increased the expression of inflammatory factors IL1β, IL6, and TNFα expression, which was reversed by TP injection. In addition, CLP operation promoted apoptosis and senescence in tissues and cells during lung injury, while TP administration removed the damaged role of CLP on lung tissues and cells. Furthermore, CLP operation or LPS (lipopolysaccharide) treatment induced dysfunction of mitochondria in lung tissues and cells, but TP contributed to recover mitochondria function, which exhibited as inhibition of ROS production inhibition and increase of ATP content and Mitochondrial membrane potential (MMP). Interestingly, DJ-1 was inhibited by CLP operation but promoted by TP treatment. Overexpression of DJ-1 reversed the injury of LPS on L2 cells and recovered mitochondria normal function. And silencing of DJ-1 in rats or alveolar epithelial cells blocked the protection effect of TP.ConclusionOur research revealed that TP protected against lung injury via upregulating of DJ-1 to improve mitochondria function, which contributed to the prevention and treatment of sepsis induced lung injury.

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K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Scientific Reports ◽

10.1038/s41598-020-78886-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tatiana Zyrianova ◽

Benjamin Lopez ◽

Riccardo Olcese ◽

John Belperio ◽

Christopher M. Waters ◽

...

Keyword(s):

Lung Injury ◽

Lung Compliance ◽

Alveolar Epithelial Cells ◽

Pharmacological Intervention ◽

Alveolar Epithelial ◽

Protein Levels ◽

Cell Counts ◽

Novel Approach ◽

Intracellular Ca ◽

Cell Depolarization

AbstractNo targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca2+ channels (CaV) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa2+ concentrations. In addition, CCL-2 secretion was decreased after L-type CaV inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

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p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00290.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. L496-L506 ◽

Cited By ~ 14

Author(s):

Nivedita Tiwari ◽

Amarnath S. Marudamuthu ◽

Yoshikazu Tsukasaki ◽

Mitsuo Ikebe ◽

Jian Fu ◽

...

Keyword(s):

Lung Injury ◽

Cigarette Smoke ◽

Lung Inflammation ◽

Cellular Adhesion ◽

Alveolar Epithelial Cells ◽

Cigarette Smoke Exposure ◽

Chronic Obstructive ◽

P53 Expression ◽

Cellular Adhesion Molecule ◽

Pai 1

We previously demonstrated that tumor suppressor protein p53 augments plasminogen activator inhibitor-1 (PAI-1) expression in alveolar epithelial cells (AECs) during chronic cigarette smoke (CS) exposure-induced lung injury. Chronic lung inflammation with elevated p53 and PAI-1 expression in AECs and increased susceptibility to and exacerbation of respiratory infections are all associated with chronic obstructive pulmonary disease (COPD). We recently demonstrated that preventing p53 from binding to the endogenous PAI-1 mRNA in AECs by either suppressing p53 expression or blockading p53 interactions with the PAI-1 mRNA mitigates apoptosis and lung injury. Within this context, we now show increased expression of the C-X-C chemokines (CXCL1 and CXCL2) and their receptor CXCR2, and the intercellular cellular adhesion molecule-1 (ICAM-1), in the lung tissues of patients with COPD. We also found a similar increase in lung tissues and AECs from wild-type (WT) mice exposed to passive CS for 20 wk and in primary AECs treated with CS extract in vitro. Interestingly, passive CS exposure of mice lacking either p53 or PAI-1 expression resisted an increase in CXCL1, CXCL2, CXCR2, and ICAM-1. Furthermore, inhibition of p53-mediated induction of PAI-1 expression by treatment of WT mice exposed to passive CS with caveolin-1 scaffolding domain peptide reduced CXCL1, CXCL2, and CXCR2 levels and lung inflammation. Our study reveals that p53-mediated induction of PAI-1 expression due to chronic CS exposure exacerbates lung inflammation through elaboration of CXCL1, CXCL2, and CXCR2. We further provide evidence that targeting this pathway mitigates lung injury associated with chronic CS exposure.

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