Abstract
BackgroundAsthma 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.MethodsWild 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.ResultsLipopolysaccharide 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.ConclusionsWhile 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.
Highlights
Asthma exacerbations are associated with the recruitment of neutrophils to the lungs
Effect of LPS on lung function in wild type and Rgs2−/− mice In initial experiments, wild type C57Bl/6 mice were exposed to aerosolized phosphate buffered saline (PBS) (20 ml) or LPS (20 ml at 150 μg/ml in PBS) administered over a 30 min period
3 h after LPS exposure, MCh challenge induced significantly greater increases in lung resistance when compared to the PBS-exposed animals (Fig. 1a)
Summary
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. PARs may signal via multiple transducers, which include Gq, as well as Gi, G12/13, and likely β-arrestin, and may contribute to various inflammatory responses [5,6,7] HDM extracts produce profound airway inflammation and AHR in mouse models of asthma [8,9,10]. Many proteases, including those in HDM or cockroach allergen, elicit inflammatory responses and, in vivo, may act via PAR2, which can couple via Gq and other transducers [7, 11], to induce inflammation and reduce lung function [12,13,14,15]. Inhibition of neutrophil elastase improved AHR and inflammation in a mouse model of airways inflammation, suggesting that neutrophil-derived proteolytic activity can be a major driver of inflammation [22]
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