Differences in respiratory syncytial virus and influenza infection in a house-dust-mite-induced asthma mouse model: consequences for steroid sensitivity (original) (raw)
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Allergy, 2016
Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics. We developed and characterized a robust, consistent and reproducible mouse model of severe exacerbation of chronic allergic asthma. Chronic allergic airway inflammation was induced following a house dust mite (HDM)-sensitization protocol. HDM-sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled Fluticasone Propionate (FP), systemic corticosteroids (Pred) or anti-IL5. Mice were sacrificed at different time points after infection: cellular accumulation and cytokines levels in the airways; PenH as a measure of airway hyperresponsiveness (AHR); lung histology and viral replication were assessed. Infection with low dose A/X31 H3N2 led to prolonged deterioration of lung fu...
Scandinavian Journal of Immunology, 2014
Non-eosinophilic asthma is characterized by infiltration of neutrophils into the lung and variable responsiveness to glucocorticoids. The pathophysiological mechanisms have not been characterized in detail. Here, we present an experimental asthma model in mice associated with non-eosinophilic airway inflammation and airway hyper-responsiveness (AHR). For this, BALB/c mice were sensitized by biolistic DNA immunization with a plasmid encoding the model antigen b-galactosidase (pFascin-bGal mice). For comparison, eosinophilic airway inflammation was induced by subcutaneous injection of bGal protein (bGal mice). Intranasal challenge of mice in both groups induced AHR to a comparable extent as well as recruitment of inflammatory cells into the airways. In contrast to bGal mice, which exhibited extensive eosinophilic infiltration in the lung, goblet cell hyperplasia and polarization of CD4 + T cells into Th2 and Th17 cells, pFascin-bGal mice showed considerable neutrophilia, but no goblet cell hyperplasia and a predominance of Th1 and Tc1 cells in the airways. Depletion studies in pFascin-bGal mice revealed that CD4 + and CD8 + cells cooperated to induce maximum inflammation, but that neutrophilic infiltration was not a prerequisite for AHR induction. Treatment of pFascin-bGal mice with dexamethasone before intranasal challenge did not affect neutrophilic infiltration, but significantly reduced AHR, infiltration of monocytes and lymphocytes as well as content of IFN-c in the bronchoalveolar fluid. Our results suggest that non-eosinophilic asthma associated predominantly with Th1/Tc1 cells is susceptible to glucocorticoid treatment. pFascin-bGal mice might represent a mouse model to study pathophysiological mechanisms proceeding in the subgroup of asthmatics with non-eosinophilic asthma that respond to inhaled steroids.
Clinical & Experimental Allergy, 2008
Background Human rhinoviruses (HRVs) and house dust mites (HDMs) are among the most common environmental factors able to induce airway inflammation in asthma. Although epidemiological studies suggest that they also synergize in inducing asthma exacerbations, there is no experimental evidence to support this, nor any information on the possible mechanisms involved. Objective To investigate their interaction on the induction of airway epithelial inflammatory responses in vitro. Methods BEAS-2B cells were exposed to activated HDM Dermatophagoides pteronyssinus major allergen I (Der p I), HRVs (HRV1b or HRV16) or both in different sequences. IL-8/CXCL8 release, intercellular adhesion molecule (ICAM)-1 surface expression and nuclear factor kB (NF-kB) translocation were evaluated. Complementary, primary human bronchial epithelial cells (HBECs) exposed to both Der p I and RVs and IL-8, IL-6, IFN-g-induced protein (IP)-10/CXCL10, IFN-l1/IL-29, regulated upon activation normal T lymphocyte expressed and secreted (RANTES)/CCL5 release were measured. Results RV and Der p I up-regulated IL-8 release, ICAM-1 expression and NF-kB translocation in BEAS-2B cells. Simultaneous exposure to both factors, as well as when cells were initially exposed to HRV and then to Der p I, resulted in further induction of IL-8 in a synergistic manner. Synergism was not observed when cells were initially exposed to Der p I and then to HRV. This was the pattern in ICAM-1 induction although the phenomenon was not synergistic. Concurrent exposure induced an early synergistic NF-kB translocation induction, differentiating with time, partly explaining the above observation. In HBECs, both HRV and Der p I induced IL-8, IL-6, IL-29 and IP-10, while RANTES was induced only by HRV. Synergistic induction was observed only in IL-8. Conclusion HRV and enzymatically active Der p I can act synergistically in the induction of bronchial epithelial IL-8 release, when HRV infection precedes or is concurrent with Der p I exposure. Such a synergy may represent an important mechanism in virus-induced asthma exacerbations.
Steroid-resistant neutrophilic inflammation in a mouse model of an acute exacerbation of asthma
2008
Neutrophilic inflammation in acute exacerbations of asthma tends to be resistant to treatment with glucocorticoids. This may be related to decreased activity and expression of histone deacetylase-2 (HDAC2), which down-regulates expression of proinflammatory genes via recruitment to the glucocorticoid receptor complex. We assessed airway inflammation and response to steroid treatment in a novel mouse model of an acute exacerbation of chronic asthma. Systemically sensitized mice received low-level challenge with aerosolized ovalbumin for 4 weeks, followed by a single moderate-level challenge to induce enhanced inflammation in distal airways. We assessed the effects of pre-treatment with dexamethasone on the accumulation of inflammatory cells in the airways, airway responsiveness to methacholine, expression and enzymatic activity of nuclear proteins including histone acetyl transferase (HAT) and HDAC2, and levels of transcripts for neutrophil chemoattractant and survival cytokines. Dexamethasone suppressed inflammation associated with eosinophil and T-lymphocyte recruitment, but did not prevent neutrophil accumulation or development of airway hyperresponsiveness. Increased activity of HAT was suppressed by steroid treatment, but the marked diminution of HDAC2 activity and increased activity of nuclear factor-kB were not reversed. Correspondingly, elevated expression of mRNA for TNF-a, granulocytemacrophage colony-stimulating factor, IL-8, and p21 waf were also not suppressed by dexamethasone. Levels of lipid peroxidation and protein nitration products were elevated in the acute exacerbation model. We conclude that impaired nuclear recruitment of HDAC2 could be an important mechanism of steroid resistance of the neutrophilic inflammation in exacerbations of asthma. Oxidative stress may contribute to decreased HDAC2 activity.
Anti-inflammatory modulation of chronic airway inflammation in the murine house dust mite model
Pulmonary Pharmacology & Therapeutics, 2008
Asthma affects 300 million people worldwide and continues to be a major cause of morbidity and mortality. Disease relevant animal models of asthma are required for benchmarking of novel therapeutic mechanisms in comparison to established clinical approaches. We demonstrate that chronic exposure of mice to house dust mite (HDM) extract results in allergic airway inflammation, that can be significantly attenuated by therapeutic intervention with phosphodiesterase 4 inhibition and corticosteroid treatment. Female BALB/c mice were administered intranasally with HDM (Dermatophagoides pteronyssinus) extract daily for five weeks, and therapeutic intervention with anti-inflammatory treatment (dexamethasone 1 mg/kg subcutaneous once daily, prednisolone 10 mg/kg orally twice daily, fluticasone 3, 10 and 30 mg intranasally twice daily, roflumilast 10 mg/kg orally twice daily and intranasally 10 and 30 mg twice daily) was initiated after three weeks of exposure. Chronic HDM extract exposure resulted in significant airway inflammation, demonstrated by bronchoalveolar lavage cell infiltration and lung tissue inflammatory gene expression by TaqMan low density array. Chronic steroid treatment significantly inhibited these parameters. In addition, roflumilast caused a significant reduction in airway inflammatory cell infiltration. We have demonstrated that chronic HDM-induced allergic inflammation can be significantly ameliorated by steroid treatment, and that phosphodiesterase 4 inhibition modulates inflammatory cell infiltration. Therefore, the murine HDM model may be a useful tool for evaluating new targets for the treatment of asthma.
Airway inflammation and illness severity in response to experimental rhinovirus infection in asthma
CHEST Journal, 2014
Original Research ASTHMA R hinoviruses (RVs) are the major cause of acute exacerbations of asthma. 1-3 Human experimental RV infection in volunteers with mild asthma is associated with augmented physiologic and infl ammatory responses to allergen challenge, 4,5 reductions in peak expiratory fl ow (PEF) 6 and FEV 1 , 7 and increases in bronchial reactivity. 8 In agreement, our own previously reported study showed that experimental RV16 infection in asthma induced signifi cant increases in bronchial reactivity, lower respiratory tract symptoms, and lung function impairment and that signifi cant changes in these outcomes did not occur in normal subjects. Regarding RV-induced airway infl ammation, two previous studies of experimental RV infection reported increases in submucosal CD3 1 lymphocytes and eosinophils in asthmatic and normal groups combined 10 and in subjects with asthma alone. 11 The increased