scholarly journals Brusatol Derivative–34 Attenuates Allergic Airway Inflammation Via Inhibition of the Spleen Tyrosine Kinase Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yasi Ding ◽  
Weibin Tang ◽  
Fei Pei ◽  
Lixia Fu ◽  
Pei Ma ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Inflammatory Cells ◽  
Nuclear Factor Κb ◽  
Spleen Tyrosine Kinase ◽  
Cytoplasmic Phospholipase A2 ◽  
Kinase Pathway

Brusatol derivative-34 (Bru-34), a derivative of brusatol, has been shown significantly anti-inflammatory activity in mice in our previously work. However, to our knowledge, there were very limited studies on how Bru-34 affected airway inflammation. Thus, in this present study, the effects and potential mechanisms of Bru-34 on allergic airway inflammation were examined both in vivo and in vitro. The results showed that Bru-34 attenuated the allergic airway inflammation in mice, with significant decreasing of the inflammatory cells and mediators in bronchoalveolar lavage fluids and attenuation of the histopathological alterations in the lung tissues. In addition, Bru-34 significantly inhibited the release of inflammatory cytokines in antigen induced rat basophilic leukemia -2H3 (RBL-2H3) cells. What’s more, Bru-34 significantly decreased the expression of spleen tyrosine kinase (Syk), p-Syk, cytoplasmic phospholipase A2 (cPLA2), p-cPLA2, nuclear factor-κB (NF-κB) and p-NF-κB both in allergic mice lung tissue and antigen induced RBL-2H3 cells. Furthermore, the collaborative effects of Bru-34 with inhibitors against Syk, cPLA2, and NF-κB, showed that Syk was an important target of Bru-34, and cPLA2 and NF-κB played important roles in the coordinated inflammatory response. In conclusion, Bru-34 could significantly modulate the allergic airway inflammation, and its potential mechanism was revealed at least partially via down-regulating of Syk-cPLA2 -NF-κB signaling.

scholarly journals HDAC2 attenuates airway inflammation by suppressing IL-17A production in HDM-challenged mice

2019 ◽  
Vol 316 (1) ◽  
pp. L269-L279 ◽  
Author(s):  
Tianwen Lai ◽  
Mindan Wu ◽  
Chao Zhang ◽  
Luanqing Che ◽  
Feng Xu ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inflammatory Cytokines ◽  
Allergic Inflammation ◽  
Allergic Airway Inflammation ◽  
Inflammatory Cells ◽  
Protective Role ◽  
In Vivo Models

Histone deacetylase (HDAC)2 is expressed in airway epithelium and plays a pivotal role in inflammatory cells. However, the role of HDAC2 in allergic airway inflammation remains poorly understood. In the present study, we determined the role of HDAC2 in airway inflammation using in vivo models of house dust mite (HDM)-induced allergic inflammation and in vitro cultures of human bronchial epithelial (HBE) cells exposed to HDM, IL-17A, or both. We observed that HDM-challenged Hdac2+/− mice exhibited substantially enhanced infiltration of inflammatory cells. Higher levels of T helper 2 cytokines and IL-17A expression were found in lung tissues of HDM-challenged Hdac2+/− mice. Interestingly, IL-17A deletion or anti-IL-17A treatment reversed the enhanced airway inflammation induced by HDAC2 impairment. In vitro, HDM and IL-17A synergistically decreased HDAC2 expression in HBE cells. HDAC2 gene silencing further enhanced HDM- and/or IL-17A-induced inflammatory cytokines in HBE cells. HDAC2 overexpresion or blocking IL-17A gene expression restored the enhanced inflammatory cytokines. Collectively, these results support a protective role of HDAC2 in HDM-induced airway inflammation by suppressing IL-17A production and might suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of allergic airway inflammation.

scholarly journals Regulation of eosinophilia and allergic airway inflammation by the glycan-binding protein galectin-1

2016 ◽  
Vol 113 (33) ◽  
pp. E4837-E4846 ◽  
Author(s):  
Xiao Na Ge ◽  
Sung Gil Ha ◽  
Yana G. Greenberg ◽  
Amrita Rao ◽  
Idil Bastan ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Binding Protein ◽  
Allergic Airway Inflammation ◽  
Inflammatory Cells ◽  
Cell Clustering ◽  
Tnf Α ◽  
Chemokine Receptor Ccr3 ◽  
Cell Adhesion Molecule 1

Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflammatory activities, functions as a proresolving mediator in autoimmune and chronic inflammatory disorders. However, its role in allergic airway inflammation has not yet been elucidated. We evaluated the effects of Gal-1 on eosinophil function and its role in a mouse model of allergic asthma. Allergen exposure resulted in airway recruitment of Gal-1–expressing inflammatory cells, including eosinophils, as well as increased Gal-1 in extracellular spaces in the lungs. In vitro, extracellular Gal-1 exerted divergent effects on eosinophils that were N-glycan– and dose-dependent. At concentrations ≤0.25 µM, Gal-1 increased eosinophil adhesion to vascular cell adhesion molecule-1, caused redistribution of integrin CD49d to the periphery and cell clustering, but inhibited ERK(1/2) activation and eotaxin-1–induced migration. Exposure to concentrations ≥1 µM resulted in ERK(1/2)-dependent apoptosis and disruption of the F-actin cytoskeleton. At lower concentrations, Gal-1 did not alter expression of adhesion molecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine receptor CCR3, but decreased CD49d and CCR3 was observed in eosinophils treated with higher concentrations of this lectin. In vivo, allergen-challenged Gal-1–deficient mice exhibited increased recruitment of eosinophils and CD3+ T lymphocytes in the airways as well as elevated peripheral blood and bone marrow eosinophils relative to corresponding WT mice. Further, these mice had an increased propensity to develop airway hyperresponsiveness and displayed significantly elevated levels of TNF-α in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and suppresses airway inflammation by inhibiting cell migration and promoting eosinophil apoptosis.

scholarly journals An in Vitro and in Vivo Study of the Effect of Dexamethasone on Immunoinhibitory Function of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells

2018 ◽  
Vol 27 (9) ◽  
pp. 1340-1351 ◽  
Author(s):  
Dan Wang ◽  
Yue-Qi Sun ◽  
Wen-Xiang Gao ◽  
Xing-Liang Fan ◽  
Jian-Bo Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Airway Inflammation ◽  
Pluripotent Stem Cell ◽  
Allergic Airway Inflammation ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent ◽  
Immunomodulatory Function

Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) represent a promising cell source for patient-specific cell therapy. We previously demonstrated that they display an immunomodulatory effect on allergic airway inflammation. Glucocorticoids are powerful anti-inflammatory compounds and widely used in the therapy of allergic diseases. However, the effect of glucocorticoids on the immunomodulatory function of iPSC-MSCs remains unknown. This study aimed to determine the effect of dexamethasone (Dex) on the immunomodulatory function of iPSC-MSCs in vitro and in vivo. A total of three human iPSC-MSC clones were generated from amniocyte-derived iPSCs. Anti-CD3/CD28-induced peripheral blood mononuclear cell (PBMC) proliferation was used to assess the effect of Dex on the immunoinhibitory function of iPSC-MSCs in vitro. Mouse models of contact hypersensitivity (CHS) and allergic airway inflammation were induced, and the levels of inflammation in mice were analyzed with the treatments of iPSC-MSCs and Dex, alone and combined. The results showed that Dex did not interfere with the immunoinhibitory effect of iPSC-MSCs on PBMC proliferation. In CHS mice, simultaneous treatment with Dex did not affect the effect of iPSC-MSCs on the inflammation, both in regional draining lymph nodes and in inflamed ear tissue. In addition, co-administration of iPSC-MSCs with Dex decreased the local expression of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in the ears of CHS mice. In the mouse model of allergic airway inflammation, iPSC-MSC treatment combined with Dex resulted in a similar extent of reduction in pulmonary inflammation as iPSC-MSCs or Dex treatment alone. In conclusion, Dex does not significantly affect the immunomodulatory function of iPSC-MSCs both in vitro and in vivo. These findings may have implications when iPSC-MSCs and glucocorticoids are co-administered.

scholarly journals FSTL1 aggravates OVA-induced allergic airway inflammation by activating NLRP3 inflammasome

2020 ◽  
Author(s):  
Yan Wang ◽  
Tian Liu ◽  
Jun-fei Wang ◽  
Bao-yi Liu ◽  
Jin-xiang Wu ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Nlrp3 Inflammasome ◽  
Allergic Airway Inflammation ◽  
Experimental Treatment ◽  
Underlying Mechanism ◽  
Whole Body ◽  
Control Group ◽  
Asthmatic Patients

Abstract Background Asthma is a common respiratory disease characterized by chronic airway inflammation. As a novel inflammatory mediator, follistatin-like protein 1 (FSTL1) can activate immune reaction, suggesting that it may contribute to inflammatory disorders such as asthma. Besides, there are growing evidences that nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) / Interleukin (IL)-1β axis participates in asthma. In this study, we investigated the role of FSTL1 in allergic airway inflammation and its underlying mechanism of activating NLRP3 inflammasome. Methods Circulating FSTL1 and IL-1β levels were quantified in serum of asthmatic patients and controls. Whole-body ablation Fstl1 heterozygous mice (Fstl1 +/- ) and control group were assessed after the experimental treatment. The effects of FSTL1 on NLRP3 inflammasome were also tested in primary macrophages of mice in vitro. Results The concentration of FSTL1 and IL-1β in serum of asthmatic patients were elevated compared with controls and were positively correlated. FSTL1 deficiency ameliorated infiltration of inflammatory cells,corresponding pathological changes,cytokine responses (IL-1β, IL-5,IL-13), mucous hypersecretion and hyper-responsiveness of airway after Ovalbumin (OVA) exposure in the mouse model. Additionally, inhibition of NLRP3 with MCC950 attenuated FSTL1-induced activation of NLRP3 inflammasome and airway inflammation in vivo and vitro. Conclusions Our data showed that FSTL1 played an important role in allergic airway inflammation by activating NLRP3 inflammasome, providing the possibility that FSTL1 could be applied as a therapeutic strategy on asthma.

Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation

Thorax ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 918-927 ◽  
Author(s):  
Yanping Wu ◽  
Haixia Chen ◽  
Nanxia Xuan ◽  
Lingren Zhou ◽  
Yinfang Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effect ◽  
Airway Inflammation ◽  
Synergistic Effects ◽  
Morphological Characteristics ◽  
Allergic Airway Inflammation ◽  
Lavage Fluid ◽  
Allergic Disorders

IntroductionEosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs).MethodsEosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation.ResultsTreatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo.ConclusionsFINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.

Antagonism of mmu-mir-106a attenuates asthma features in allergic murine model

2012 ◽  
Vol 113 (3) ◽  
pp. 459-464 ◽  
Author(s):  
Amit Sharma ◽  
Manish Kumar ◽  
Tanveer Ahmad ◽  
Ulaganathan Mabalirajan ◽  
Jyotirmoi Aich ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inflammatory Diseases ◽  
Allergic Airway Inflammation ◽  
Interleukin 10 ◽  
Dependent Manner ◽  
Th2 Response ◽  
Lung Histology ◽  
Health And Disease

MicroRNAs (miRs) regulate immunological pathways in health and disease, and a number of miRs have been shown to be altered in mouse models of asthma. The secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine, has been shown to be defective in many inflammatory diseases including asthma. We recently demonstrated that miR-106a inhibits IL-10 in a post-transcriptional manner. In this study, we investigated the effect of inhibition of mmu-miR106a in asthmatic condition to find its possible role as a therapeutic target. Our in vitro experiments with mouse macrophage, RAW264.7, revealed that mmu-miR-106a potentially decreased IL-10 along with increase in proinflammatory cytokine. Furthermore, administration of mmu-miR-106a to naive mice reduced IL-10 levels in lungs in a dose-dependent manner without altering lung histology. Most interestingly, knockdown of mmu-miR-106a in an established allergic airway inflammation has significantly alleviated most of the features of asthma such as airway hyperresponsiveness, airway inflammation, increased Th2 response, goblet cell metaplasia, and subepithelial fibrosis along with increase in IL-10 levels in lung. This represents the first in vivo proof of a miRNA-mediated regulation of IL-10 with a potential to reverse an established asthmatic condition.

scholarly journals Impaired TNF/TNFR2 signaling enhances Th2 and Th17 polarization and aggravates allergic airway inflammation

2017 ◽  
Vol 313 (3) ◽  
pp. L592-L601 ◽  
Author(s):  
Xiao-Ming Li ◽  
Xi Chen ◽  
Wen Gu ◽  
Yi-Jia Guo ◽  
Yi Cheng ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Airway Inflammation ◽  
Tumor Necrosis Factor Receptor ◽  
Allergic Airway Inflammation ◽  
Lavage Fluid ◽  
T Cell Differentiation ◽  
Airway Diseases

CD4+ T-cell differentiation plays an important role in allergic airway diseases. Tumor necrosis factor receptor 2 (TNFR2) has been shown to regulate CD4+ T-lymphocyte differentiation, but its role in allergic airway inflammation is not clear. Here, we investigated the role of TNFR2 in allergic airway inflammation. The mouse model was generated by immunization with ovalbumin and intranasal administration of TNFR2 antibody. Airway inflammation and CD4+ T-cell differentiation were measured in vivo and in vitro. Inhibited TNFR2 signaling aggravated airway inflammation and increased the expression of inflammatory cytokines (IL-4, IL-5, IL-17, and TNF-α) in serum and bronchoalveolar lavage fluid. Impaired TNFR2 signaling promoted Th2 and Th17 polarization but inhibited Th1 and CD4+CD25+ T-cell differentiation in vivo. Furthermore, TNFR2 signaling inhibition promoted Th2 and Th17 polarization in vitro, which may occur through the activation of TNF receptor-associated factor 2 and NF-κB signaling. Therefore, our findings indicate that impaired TNF/TNFR2 signaling enhances Th2 and Th17 polarization and aggravates allergic airway inflammation.

scholarly journals Essential Role of Nuclear Factor κB in the Induction of Eosinophilia in Allergic Airway Inflammation

1998 ◽  
Vol 188 (9) ◽  
pp. 1739-1750 ◽  
Author(s):  
Liyan Yang ◽  
Lauren Cohn ◽  
Dong-Hong Zhang ◽  
Robert Homer ◽  
Anuradha Ray ◽  
...  
Keyword(s):  
T Cell ◽  
Airway Inflammation ◽  
Molecular Mechanisms ◽  
Allergic Airway Inflammation ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Interleukin 5 ◽  
T Helper 2 ◽  
Inflammatory Protein

The molecular mechanisms that contribute to an eosinophil-rich airway inflammation in asthma are unclear. A predominantly T helper 2 (Th2)-type cell response has been documented in allergic asthma. Here we show that mice deficient in the p50 subunit of nuclear factor (NF)- κB are incapable of mounting eosinophilic airway inflammation compared with wild-type mice. This deficiency was not due to a block in T cell priming or proliferation in the p50−/− mice, nor was it due to a defect in the expression of the cell adhesion molecules VCAM-1 and ICAM-1 that are required for the extravasation of eosinophils into the airways. The major defects in the p50−/− mice were the lack of production of the Th2 cytokine interleukin 5 and the chemokine eotaxin, which are crucial for proliferation and for differentiation and recruitment, respectively, of eosinophils into the asthmatic airway. Additionally, the p50−/− mice were deficient in the production of the chemokines macrophage inflammatory protein (MIP)-1α and MIP-1β that have been implicated in T cell recruitment to sites of inflammation. These results demonstrate a crucial role for NF-κB in vivo in the expression of important molecules that have been implicated in the pathogenesis of asthma.

Resistin-like molecule-β is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung

2007 ◽  
Vol 293 (2) ◽  
pp. L305-L313 ◽  
Author(s):  
Anil Mishra ◽  
Meiqin Wang ◽  
James Schlotman ◽  
Nikolaos M. Nikolaidis ◽  
Charles W. DeBrosse ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Goblet Cell ◽  
Allergic Airway Inflammation ◽  
Mouse Lung ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Leukocyte Accumulation

Resistin-like molecule (RELM)-β is a cysteine-rich cytokine implicated in insulin resistance and asthmatic responses, but its function remains an enigma. We now report that RELM-β has a role in promoting airway inflammation and lung remodeling in the mouse lung. RELM-β is strongly induced by diverse allergens and T helper type 2 (Th2) cytokines by an IL-13- and STAT6-dependent mechanism. To understand the in vivo role of RELM-β, we delivered recombinant murine RELM-β intratracheally to naïve mice. RELM-β induced dose-dependent leukocyte accumulation (most prominently involving macrophages) and goblet cell hyperplasia. The most prominent effect induced by RELM-β was increased perivascular and peribronchial collagen deposition. Mice genetically deficient in RELM-β had reduced accumulation of collagen and goblet cell hyperplasia in an experimental model of allergic airway inflammation. In vitro experiments demonstrated that RELM-β had fibroblast motogenic activity. These results identify RELM-β as a Th2-associated cytokine with potent inflammatory and remodeling activity.

scholarly journals Lysophosphatidic Acid Regulates the Differentiation of Th2 Cells and Its Antagonist Suppresses Allergic Airway Inflammation

2020 ◽  
Vol 182 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Mayo Kondo ◽  
Toshifumi Tezuka ◽  
Hirohisa Ogawa ◽  
Kazuya Koyama ◽  
Hiroki Bando ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Lysophosphatidic Acid ◽  
Therapeutic Potential ◽  
Allergic Inflammation ◽  
Allergic Airway Inflammation ◽  
Th2 Cells ◽  
Nasal Administration ◽  
Lpa Receptor

<b><i>Background:</i></b> Lysophosphatidic acid (LPA), a prototypic member of a large family of lysophospholipids, has been recently shown to play a role in immune responses to respiratory diseases. The involvement of LPA in allergic airway inflammation has been reported, but the mechanism remains unclear. <b><i>Object:</i></b> We analyzed the biological activity of LPA in vitro and in vivo and investigated its role in allergic inflammation in mice using an LPA receptor 2 (LPA2) antagonist. <b><i>Methods:</i></b> We used a murine model with acute allergic inflammation, in which mice are sensitized and challenged with house dust mite, and analyzed airway hyperresponsiveness (AHR), pathological findings, Th2 cytokines, and IL-33 in bronchoalveolar lavage fluid (BALF) and lung homogenates. The effect of LPA on Th2 differentiation and cytokine production was examined in vitro using naive CD4<sup>+</sup> T cells isolated from splenocytes. We also investigated in vivo the effects of LPA on intranasal administration in mice. <b><i>Results:</i></b> The LPA2 antagonist suppressed the increase of AHR, the number of total cells, and eosinophils in BALF and lung tissue. It also decreased the production of IL-13 in BALF and IL-33 and CCL2 in the lung. LPA promoted Th2 cell differentiation and IL-13 production by Th2 cells in vitro. Nasal administration of LPA significantly increased the number of total cells and IL-13 in BALF via regulating the production of IL-33 and CCL-2-derived infiltrating macrophages. <b><i>Conclusion:</i></b> These findings suggest that LPA plays an important role in allergic airway inflammation and that the blockade of LPA2 might have therapeutic potential for bronchial asthma.

Sign in / Sign up

Export Citation Format

Share Document