Anti-asthmatic effect of nafamostat is associated with modulated expression of pro-inflammatory genes, reduced eosinophil infiltration and attenuated airway hyperreactivity
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PROVIDER: PRJNA926995 | ENA |
REPOSITORIES: ENA
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Project description:Asthma is typically characterized by an imbalance between the expression of proteases and of inhibitors capable of neutralizing such enzymes. Hence, an attractive option for intervening with asthma could be to interfere with asthma-associated proteases. In this study, we exploited this option by assessing the impact of nafamostat, a serine protease inhibitor with known capacity to neutralize mast cell tryptase, on the manifestations of airway responses in a house dust mite (HDM)-based model of experimental asthma. Our findings reveal that nafamostat efficiently suppressed the airway hyperreactivity in HDM-sensitized mice, which was accompanied by a profound reduction in the infiltration of eosinophils and lymphocytes to the airways, and also by suppression of the levels of proinflammatory compounds within the airway lumen.Further, nafamostat caused a marked reduction of eosinophil inflammation in the lung tissue, and we also show that nafamostat had a dampening impact on goblet cell hyperplasia and smooth muscle layer thickening in the lungs of HDM-sensitized animals. To obtain deeper insight into the mechanism by which nafamostat affects parameters of allergic airway inflammation, a transcriptomic analysis was conducted. This analysis revealed, as expected, that the HDM sensitization caused an upregulated expression of numerous proinflammatory genes. Further, the transcriptomic analysis showed that nafamostat suppressed the levels of multiple proinflammatory genes, with a particular impact on genes related to asthma. Altogether, this study provides extensive insight into the ameliorating effect of nafamostat on experimental asthma, and our findings can thereby provide a basis for the further evaluation of nafamostat as a potential therapeutic agent in human asthma.
2023-05-10 | GSE223629 | GEO
Project description:IntroductionAsthma is characterized by an imbalance between proteases and their inhibitors. Hence, an attractive therapeutic option could be to interfere with asthma-associated proteases. Here we exploited this option by assessing the impact of nafamostat, a serine protease inhibitor known to neutralize mast cell tryptase.MethodsNafamostat was administered in a mouse model for asthma based on sensitization by house dust mite (HDM) extract, followed by the assessment of effects on airway hyperreactivity, inflammatory parameters and gene expression.ResultsWe show that nafamostat efficiently suppressed the airway hyperreactivity in HDM-sensitized mice. This was accompanied by reduced infiltration of eosinophils and lymphocytes to the airways, and by lower levels of pro-inflammatory compounds within the airway lumen. Further, nafamostat had a dampening impact on goblet cell hyperplasia and smooth muscle layer thickening in the lungs of HDM-sensitized animals. To obtain deeper insight into the underlying mechanisms, a transcriptomic analysis was conducted. This revealed, as expected, that the HDM sensitization caused an upregulated expression of numerous pro-inflammatory genes. Further, the transcriptomic analysis showed that nafamostat suppressed the levels of multiple pro-inflammatory genes, with a particular impact on genes related to asthma.DiscussionTaken together, this study provides extensive insight into the ameliorating effect of nafamostat on experimental asthma, and our findings can thereby provide a basis for the further evaluation of nafamostat as a potential therapeutic agent in human asthma.
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Project description:Dietary long-chain omega 3 fatty acids modify sphingolipid metabolism to facilitate asthmatic airway hyperreactivity
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Project description:<p>Eosinophils are the predominant immune cells implicated in the pathogenesis of asthma, highlighting the need for strategies to mitigate their effects. While previous studies have indicated a potential relationship between lysosomes and eosinophils, the precise role of lysosomes in eosinophil activation during asthma remains insufficiently understood. In this study, we demonstrated that lysosomal acidity and cathepsin L (CTSL) activity in eosinophils were elevated in asthmatic patients and mouse models. Genetic deletion or pharmacological inhibition of CTSL in eosinophils significantly attenuated allergic airway inflammation in vivo and suppressed eosinophil activation in vitro. CTSL in eosinophils promoted type 2 immune responses by upregulating arginase 1 (ARG1) expression and interacting with it, thereby enhancing ARG1 activity and altering arginine metabolism during eosinophil activation. This metabolic shift led to increased production of ornithine, which exacerbated inflammatory processes. Furthermore, lysosomal acidity and CTSL activity correlated with disease severity in asthmatic patients. Our findings reveal that lysosomal acidity and CTSL facilitate eosinophil activation through arginine metabolism, thereby promoting allergic airway inflammation.</p>
2025-09-15 | MTBLS13001 | MetaboLights
Project description:Increased intestinal permeability can exacerbate psoriasis, a systemic inflammatory disease with complex pathogenesis. Using a mouse model of psoriasis elicited by the TLR7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by small-intestinal inflammatory changes associated with eosinophil degranulation which led to impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were accelerated in mice that are prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells treated with media containing eosinophil granule proteins exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal inflammatory changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by eosinophil transfer. Imiquimod levels and eosinophil distribution were positively correlated in the intestine. TLR7-deficient mice did not show intestinal eosinophil degranulation and exhibited attenuated skin and small-intestinal inflammation following imiquimod application. These results suggest a TLR7-dependent bidirectional skin-to-gut communication in psoriatic inflammation, and that intestinal inflammatory changes can accelerate psoriasis.
2024-04-30 | GSE237610 | GEO
Project description:Eosinophilic esophagitis (EoE) is a chronic, inflammatory, and antigen-driven disease of the esophagus. Total transcriptome data revealed alterations in the endocannabinoid system (ECS), in particular, downregulation of monoacylglycerol lipase (MGL) in biopsies of patients with active EoE. We investigated the consequence of MGL downregulation in mucosal biopsies of patients, and its implications for EoE development, such as recruitment of eosinophils. Levels of MGL substrate 2-arachidonoylglycerol (2-AG), MGL enzyme activity and MGL co-localization with epithelial cells were determined in mucosal esophageal biopsies of EoE patients. Supernatant of human primary esophageal epithelial cells was used to determine eosinophil migration and activation. An inducible mouse model of EoE was used to test MGL inhibition and cannabinoid (CB) receptor antagonism in vivo. MGL expression in esophageal epithelial cells from active EoE patients is decreased, while 2-AG is increased compared to controls. Inhibition of MGL in epithelial cells leads to a pro-inflammatory phenotype capable of attracting eosinophils via CB2. Similarly, the EoE mouse model indicates that absence of MGL results in higher eosinophil infiltration. Targeting CB2 reduced the number of infiltrating eosinophils in the esophagi of mice. This study is the first of its kind to investigate the involvement of altered expression of ECS components in EoE, and partly explains recent findings of more inflammatory features post EoE-treatment in cannabis users. Our findings could pave the way for research into alternative treatment options for EoE and call for caution regarding the use of cannabinoids in EoE.
2025-05-08 | GSE282590 | GEO
Project description:Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases. Here, we aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR). Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria Alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls.Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.
2024-04-16 | GSE264060 | GEO
Project description:The endocannabinoid system drives eosinophil infiltration during eosinophilic esophagitis
| PRJNA1189431 | ENA
Project description:Asthma is a T helper 2 (Th2) cell-associated chronic inflammatory diseases characterized with airway obstruction, increased mucus production, and eosinophil infiltration. Conventional medications for asthma treatment cannot fully control the symptoms, and potential side effects are also the concerns. Thus, complement or alternative medicine (CAM) became a new option for asthma management. Ding Chuan Tang (DCT) is a traditional Chinese herbal decoction applied mainly for patients with coughing, wheezing, chest tightness, and asthma. Previously, DCT has been proved to improve children airway hyperresponsiveness (AHR) in a randomized and double-blind clinical trial. However, the mechanisms of how DCT alleviates AHR remain unclear. Since asthmatic features such as eosinophil infiltration, IgE production, and mucus accumulation are relative with Th2 responses, we hypothesized that DCT may attenuate asthma symptoms through regulating Th2 cells. Ovalbumin (OVA) was used as a stimulant to sensitize BALB/c mice to establish an asthmatic model. AHR was detected one day before sacrifice. BALF and serum were collected for immune cell counting and antibody analysis. Splenocytes were cultured with OVA in order to determine Th2 cytokine production. Lung tissues were collected for histological and gene expression analyses. Our data reveal that DCT can attenuate AHR and eosinophil accumulation in the 30-day sensitization asthmatic model. Histological results demonstrated that DCT can reduce cell infiltration and mucus production in peribronchial and perivascular site. In OVA-stimulated splenocyte cultures, a significant reduction of IL-5 and IL-13 in DCT-treated mice suggests that DCT may alleviate Th2 responses. In conclusion, the current study demonstrates that DCT has the potential to suppress allergic responses through the reduction of mucus production, eosinophil infiltration, and Th2 activity in asthma.
| S-EPMC8478538 | biostudies-literature
Project description:To identify regulators of homeostatic eosinophilopoiesis in mice, we took a global approach to identify genome-wide transcriptome and epigenome changes that occur during homeostasis at critical developmental stages, including eosinophil-lineage commitment (eosinophil progenitor [EoP] compared to granulocyte-monocyte progenitor [GMP]) and lineage maturation (eosinophil compared to EoP). Our analyses revealed markedly greater transcriptome alterations associated with eosinophil maturation (1199 genes) compared to eosinophil-lineage commitment (490 genes), highlighting the greater transcriptional investment necessary for differentiation. Our analyses also delineated a 976 gene eosinophil-lineage transcriptome that included a repertoire of 56 transcription factors, many of which have never previously been associated with eosinophils. Epigenomic studies revealed that genes that were specifically induced with eosinophil-lineage commitment in EoPs were “poised” with active chromatin marks in GMPs, despite not being expressed in GMPs. In contrast, a majority of the genes that were highly and specifically induced with maturation in eosinophils was not associated with poised chromatin, suggesting distinct epigenetic regulation between genes induced with lineage commitment compared to genes induced with cell maturation during eosinophil development.
2015-08-13 | GSE69707 | GEO