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Overexpression of Dimethylarginine Dimethylaminohydrolase 1 Attenuates Airway Inflammation in Mouse Models of Asthma

ABSTRACT: Levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are increased in lung, sputum, exhaled breath condensate and plasma samples from asthma patients. ADMA is metabolized primarily by dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2. We determined the effect of DDAH1 overexpression on development of allergic inflammation in mouse models of asthma. Wild type and DDAH1-transgenic mice were challenged with PBS or house dust mite (HDM). Airway inflammation was assessed by bronchoalveolar lavage (BAL) total and differential cell counts. Gene expression in lungs was determined by RNA-Seq and RT-quantitative PCR (qPCR). The expression of DDAH1 and DDAH2 was decreased in the lungs of mice following HDM exposure. Transgenic overexpression of DDAH1 resulted in decreased BAL total cell and eosinophil numbers following HDM exposure. Total IgE levels in serum and BAL fluid were decreased in HDM-exposed DDAH1-transgenic mice compared to HDM-exposed wild type mice. RNA-Seq results showed downregulation of genes in inducible nitric oxide synthase (iNOS) signaling pathway in PBS-treated DDAH1 transgenic mice versus PBS-treated wild type mice and downregulation of genes in IL-13/FOXA2 signaling pathway in HDM-treated DDAH1 transgenic mice versus HDM-treated wild type mice. Our findings suggest that decreased expression of DDAH1 in airway epithelial cells may contribute to allergic asthma and overexpression of DDAH1 attenuates allergen-induced airway inflammation through modulation of Th2 responses. mRNA profiles of WT and DDAH1-transgenic mice treated with PBS or house dust mite (HDM).

ORGANISM(S): Mus musculus

SUBMITTER: Jing Chen

PROVIDER: E-GEOD-49047 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Overexpression of Dimethylarginine Dimethylaminohydrolase 1 Attenuates Airway Inflammation in a Mouse Model of Asthma

Project description:Levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are increased in lung, sputum, exhaled breath condensate and plasma samples from asthma patients. ADMA is metabolized primarily by dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2. We determined the effect of DDAH1 overexpression on development of allergic inflammation in a mouse model of asthma. The expression of DDAH1 and DDAH2 in mouse lungs was determined by RT-quantitative PCR (qPCR). ADMA levels in bronchoalveolar lavage fluid (BALF) and serum samples were determined by mass spectrometry. Wild type and DDAH1-transgenic mice were intratracheally challenged with PBS or house dust mite (HDM). Airway inflammation was assessed by bronchoalveolar lavage (BAL) total and differential cell counts. The levels of IgE and IgG1 in BALF and serum samples were determined by ELISA. Gene expression in lungs was determined by RNA-Seq and RT-qPCR. Our data showed that the expression of DDAH1 and DDAH2 was decreased in the lungs of mice following HDM exposure, which correlated with increased ADMA levels in BALF and serum. Transgenic overexpression of DDAH1 resulted in decreased BAL total cell and eosinophil numbers following HDM exposure. Total IgE levels in BALF and serum were decreased in HDM-exposed DDAH1-transgenic mice compared to HDM-exposed wild type mice. RNA-Seq results showed downregulation of genes in the inducible nitric oxide synthase (iNOS) signaling pathway in PBS-treated DDAH1-transgenic mice versus PBS-treated wild type mice and downregulation of genes in IL-13/FOXA2 signaling pathway in HDM-treated DDAH1-transgenic mice versus HDM-treated wild type mice. Our findings suggest that decreased expression of DDAH1 and DDAH2 in the lungs may contribute to allergic asthma and overexpression of DDAH1 attenuates allergen-induced airway inflammation through modulation of Th2 responses.

2013-12-03 | GSE49047 | GEO

Targeting mitochondrial reactive oxygen species alleviates allergic airway disease in a mouse model of obese allergic asthma

Project description:Obesity is associated with severe, difficult to control asthma, and increased airway oxidative stress. Mitochondrial reactive oxygen species (mROS) are an important source of oxidative stress leading us to hypothesize that targeting mROS in obese allergic asthma might be an effective treatment strategy. Using a mouse model of house dust mite (HDM) induced allergic airway disease in mice fed a low- (LFD) or high-fat diet (HFD), and the mitochondrial antioxidant MitoQuinone (MitoQ); we investigated the effects of obesity and mROS on airway inflammation, remodelling and airway hyperreactivity (AHR). HDM induces airway inflammation, remodelling and hyperreactivity in both lean and obese mice. Obese allergic mice showed increased lung tissue eotaxin levels, airway tissue eosinophilia and AHR when compared to lean allergic mice. MitoQ reduced markers of airway inflammation, remodelling and hyperreactivity in both lean and obese allergic mice, and tissue eosinophilia in obeseHDM mice. mROS regulates cell signalling by protein oxidation of multiple downstream targets: MitoQ reduced HDM-induced cysteine-sulfenylation of several proteins including those involved in the unfolded protein response (UPR). In summary, mROS mediates the development of allergic airway disease and hence MitoQ might be effective for the treatment for asthma, and specific features of obese asthma.

2023-06-02 | PXD029715 | Pride

Lung biopsies from sensitized or control rhesus macaques

Project description:The aim of this study was to investigate differential expression in a house dust mite (HDM) exposure model of asthma in rhesus macaques. HDM sensitization was performed by subcutaneous injection of HDM followed by intranasal HDM for 2-3 hours twice a week. Animals were mock-sensitized (PBS) or sensitized to HDM antigen. Gene expression was measured in lung biopsies before and fifteen weeks after treatment.

2011-11-30 | E-GEOD-23327 | biostudies-arrayexpress

Airway and parenchyma RNA sequencing in a mouse model of asthma chronic obstructive pulmonary disease overlap

Project description:To profile airway and parenchyma transcriptomes in our mouse model of asthma chronic obstructive pulmonary disease overlap, we employed RNA-Seq (TruSeq Stranded mRNA sample preparation, NovaSeq 6000, 20 million 100 bp single reads) as a discovery tool to identify mRNAs of interest in the development of experimental asthma chronic obstructive pulmonary disease overlap. Experimental asthma: Some mice were sensitized and challenged intranasally with house dust mite (HDM) extract 5 days per week for 3 weeks. In other mice, this was HDM treatment 3 times/week from weeks 4-11. Controls received phosphate buffered saline (PBS). Experimental chronic obstructive pulmonary disease (COPD): Mice were exposed to cigarette smoke (CS) twice per day, 5 days per week for 8 weeks. Control mice were exposed to normal air (AIR). Experimental asthma-COPD overlap (ACO): Mice were sensitized and challenged intranasally with HDM or PBS. From weeks 4-11, mice were also exposed to CS or AIR. Treatment with dexamethasone (DEX): Separate groups of mice were treated with DEX during week 11. Lungs were excised, airway and parenchyma tissue were isolated through blunt dissection, and total RNA isolated.

2023-02-01 | GSE199853 | GEO

Effects of aeroallergen challenge on inducible and constitutive lower airway mast cells

Project description:This study are compares the transcriptomes of lower airway constitutive connective tissue mast cells (MCs), characterized by low expression of b7 integrin (B7low), and induced mucosal MCs, characterized by high b7 integrin (B7hi) at rest and in response to repeated inhalation of house dust mite extract (HDM). Lower airway b7hi and b7low MCs were flow cytometrically isolated from female 5-7 week old C57BL/6 mice following 6 challenges (2x/week for three weeks) with saline (PBS) or 3 ug house dust mite extract (HDM). Each sample is derived from pooled lung digests from three mice to reduce experimental variance. Samples were sequenced on an Illumina NextSeq 500

2020-07-29 | GSE155299 | GEO

In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome

Project description:Introduction: Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. Methods: In a house dust mite (HDM) model of allergic airway disease, we measured airway hyperresponsiveness (AHR) and airway inflammation between mice exposed prenatally to cigarette smoke (CS) or filtered air (FA). DNA methylation and gene expression were then measured in lung tissue. Results: We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM-treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs (Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3) are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Conclusions: Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease, however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease. Lung DNA methylation profiles of mice exposed in utero to cigarette smoke (CS) then treated with house dust mite (HDM, n = 8) or saline (n = 6), or exposed in utero to filtered air (FA) then treated with HDM (n = 9) or saline (n = 6)

2015-11-19 | E-GEOD-71718 | biostudies-arrayexpress

Coxsackievirus Adenovirus Receptor co-ordinates pro-inflammatory responses in the lung epithelium

Project description:Airway inflammation and remodelling are key pathophysiologic features process in many respiratory conditions such as asthma. An intact epithelial cell layer is crucial to maintain lung homeostasis, and this depends on intercellular adhesion. The Coxsackievirus Adenovirus Receptor (CAR) is highly expressed in the epithelium where it modulates cell-cell adhesion stability and acts as a receptor for immune cells to facilitate transepithelial migration. Here we investigated the mechanistic role of CAR in mediating responses to the common aeroallergen House Dust Mite (HDM). We demonstrate that administration of HDM in mice lacking CAR in the respiratory epithelium leads to loss of peri-bronchial inflammatory cell infiltration, fewer goblet-cells, decreased IL-4 and IL-13 levels and reduced matrix remodelling. In vitro analysis in human lung epithelial cells confirmed that loss of CAR led to reduced HDM-dependent inflammatory cytokine release leading to reduced inflammatory cell transmigration. Moreover, CAR was required for HDM-induced TGF release leading to enhanced airway smooth muscle cell proliferation and matrix production. Our data demonstrates that CAR is a novel central co-ordinator of lung inflammation through a dual role in leukocyte recruitment and tissue remodelling and may represent an important target for future therapeutic development in lung inflammatory diseases.

2022-09-20 | PXD029237 | Pride

Transcriptomic analysis in airway epithelial cells in HDM-sensitized STAT3-WT and STAT3-cKO mice

Project description:Purpose: To elucidate the roles of airway epithelial STAT3 in allergic airway inflammation. Method: Doxycycline-induced airway epithelial cells-specific STAT3-deficient mice (STAT3-cKO) and their genetic control mice (STAT3-WT) were sensitized intratracheally twice with house dust mite (HDM) extract or PBS at a 7-day interval. Airway epithelial cells were isolated by a cell sorter 48 h after the last senstization. N=2 each. Results: Using an optimized data analysis workflow, 206 transcripts showed differential expression between HDM-treated STAT3-WT and STAT3-cKO with adjusted p value <0.05.

2022-04-01 | GSE190345 | GEO

Alteration in gene expression in the lung following neonatal RSV infection

Project description:mRNA expression data from BALB/c mice which were infected intranasally with Respiratory Syncytial Virus (or Hep-2 cell lysate control) at 1 week old and challenged with PBS or house dust mite (HDM) extract as adults. Experimental groups: RH – neonatal RSV, adult HDM, RP – neonatal RSV, adult PBS, HH – neonatal Hep-2, adult HDM and HP – neonatal Hep-2, adult PBS.

2019-03-19 | E-MTAB-3654 | biostudies-arrayexpress

A regulatory CD9+ B cell subset controls HDM-induced allergic airway inflammation

Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma. IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) in control mice + IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) from asthmatic allergic (HDM) mice

2015-03-01 | E-GEOD-57772 | biostudies-arrayexpress

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