Browsing by Author "George, Tresa"

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    A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation
    (2018-10-01) George, Tresa; Chakraborty, Mainak; Giembycz, Mark A; Newton, Robert
    Abstract Background Asthma exacerbations are associated with the recruitment of neutrophils to the lungs. These cells release proteases and mediators, many of which act at G protein-coupled receptors (GPCRs) that couple via Gq to promote bronchoconstriction and inflammation. Common asthma therapeutics up-regulate expression of the regulator of G protein signalling (RGS), RGS2. As RGS2 reduces signaling from Gq-coupled GPCRs, we have defined role(s) for this GTPase-activating protein in an acute neutrophilic model of lung inflammation. Methods Wild type and Rgs2−/− C57Bl6 mice were exposed to nebulized lipopolysaccharide (LPS). Lung function (respiratory system resistance and compliance) was measured using a SCIREQ flexivent small animal ventilator. Lung inflammation was assessed by histochemistry, cell counting and by cytokine and chemokine expression in bronchoalveolar lavage (BAL) fluid. Results Lipopolysaccharide inhalation induced transient airways hyperreactivity (AHR) and neutrophilic lung inflammation. While AHR and inflammation was greatest 3 h post-LPS exposure, BAL neutrophils persisted for 24 h. At 3 h post-LPS inhalation, multiple inflammatory cytokines (CSF2, CSF3, IL6, TNF) and chemokines (CCL3, CCL4, CXCL1, CXCL2) were highly expressed in the BAL fluid, prior to declining by 24 h. Compared to wild type counterparts, Rgs2−/− mice developed significantly greater airflow resistance in response to inhaled methacholine (MCh) at 3 h post-LPS exposure. At 24 h post-LPS exposure, when lung function was recovering in the wild type animals, MCh-induced resistance was increased, and compliance decreased, in Rgs2−/− mice. Thus, Rgs2−/− mice show AHR and stiffer lungs 24 h post-LPS exposure. Histological markers of inflammation, total and differential cell counts, and major cytokine and chemokine expression in BAL fluid were similar between wild type and Rgs2−/− mice. However, 3 and 24 h post-LPS exposure, IL12B expression was significantly elevated in BAL fluid from Rgs2−/− mice compared to wild type animals. Conclusions While Rgs2 is bronchoprotective in acute neutrophilic inflammation, no clear anti-inflammatory effect was apparent. Nevertheless, elevated IL12B expression in Rgs2−/− animals raises the possibility that RGS2 could dampen Th1 responses. These findings indicate that up-regulation of RGS2, as occurs in response to inhaled corticosteroids and long-acting β2-adrenoceptor agonists, may be beneficial in acute neutrophilic exacerbations of airway disease, including asthma.
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    Investigation into the Bronchoprotective and Anti-inflammatory Properties of RGS2
    (2016) George, Tresa; Newton, Robert; Giembycz, Mark; Kelly, Margaret
    The clinical management of asthma involves treatment with inhaled corticosteroids (ICS) and long-acting β2-adrenoceptor agonists (LABAs). Regulator of G-protein signalling (RGS) 2 inhibits signalling from Gq protein-coupled receptors. In humans, combinations of a glucocorticoid and a LABA synergistically enhanced the expression of RGS2. In mice, 3 weeks of HDM challenge or 30 min of LPS challenge reduced lung function and induced airways inflammation. Compared to wild-type, Rgs2-/- mice showed significantly increased airways resistance and reduced compliance, in both HDM- and LPS-challenges. There was no difference between wild-type and Rgs2-/- mice in HDM-induced and LPS-induced inflammation. There was a trend towards increased inflammatory cell counts in the BALF of Rgs2-/- compared to wild-type. There was a trend towards increased expression for many HDM-induced cytokines/chemokines in Rgs2-/-. There was no difference between wild-type and Rgs2-/- mice in LPS-induced expression of cytokines/chemokines. These data show Rgs2 is bronchoprotective in HDM-induced inflammation and suggest a modest anti-inflammatory role. Rgs2 is bronchoprotective in LPS-induced inflammation, but more studies are required to address a possible anti-inflammatory role. If applicable to humans, these data suggest that therapeutics, for example ICS/LABA combination therapies, which are designed to maximize RGS2 expression, will be beneficial for asthma control and management.