5 research outputs found

    Compartmental and Temporal Dynamics of Chronic Inflammation and Airway Remodelling in a Chronic Asthma Mouse Model

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    <div><p>Background</p><p>Allergic asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes.</p><p>Methods</p><p>Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, goblet cell hyperplasia, collagen deposition and smooth muscle thickening.</p><p>Results</p><p>Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued.</p><p>Conclusions</p><p>Utilising a chronic model of experimental asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy.</p></div

    Schematic representation of treatment protocol.

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    <p>Mice were sensitised to OVA by three intraperitoneal (i.p.) injections on days 0, 14 and 21 with OVA absorbed to alum. Mice were sensitised and challenged with aerosolised OVA twice weekly for up to 18 weeks as indicated. Control mice were sensitised and challenged with PBS. Analysis was performed after 6, 8, 12, 14, 16 and 18 weeks of challenge (Protocol A). To investigate the resolution of airway inflammation and remodelling, OVA was replaced with PBS after 12 weeks for either 4 or 8 weeks (Protocol B). In a third study, inhaled corticosteroids (ICS) were given intranasally (i.n.) starting after 6 weeks of OVA challenge for 4 weeks (Protocol C).</p

    Inhaled corticosteroids attenuate some but not all characteristics of chronic asthma.

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    <p>Mice were sensitised and challenged for six weeks with PBS or OVA (black bars). OVA treatment was continued for another eight weeks (light grey bars), with or without parallel treatment with inhaled corticosteroids (ICS). OVA treatment was then continued for another 4 weeks without ICS application (dark grey bars) (Protocol C). Data are presented as mean ± SEM of n = 6–8 animals per group, *p≤0.05, **p≤0.01, ***p≤0.001.</p

    Resolution of airway tissue inflammation and remodelling following chronic allergen exposure.

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    <p>Chronic asthma was established by challenging OVA sensitized mice for 12 weeks twice weekly. OVA challenge was then discontinued and replaced with PBS for four or eight weeks. Outcome measurements were made at either 12 (+ 0), 16 (+ 4) or 20 (+ 8) weeks of challenge (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085839#pone-0085839-g001" target="_blank">Figure 1</a>, Protocol B). (A) Representative photomicrographs of haematoxylin & eosin (H&E) stained sections (arrows indicate eosinophils, (B) immunohistochemical staining of CD3, (C) periodic acid-Schiff (PAS), (D) Sirius Red staining and (E) immunohistochemical staining of smooth muscle actin (SMA). (F) Histological quantification of lung inflammation, (G) eosinophil numbers as determined by morphological criteria in H&E stained lung sections, (H) CD3<sup>+</sup> lymphocytes, (I) fraction of basal membrane (BM) covered by goblet cells, (J) collagen deposition and (K) SMA thickness. Box and whisker plots show mean and percentiles of n = 6–8 animals per group, *p≤0.05, **p≤0.01, ***p≤0.001.</p

    Chronic allergen exposure induces airway inflammation and remodelling.

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    <p>Mice were challenged with OVA for up to 18 weeks (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085839#pone-0085839-g001" target="_blank">Figure 1</a>, Protocol A) and analysed for airway inflammation, as determined by (A) BALF cell counts and morphometric quantification of peribronchial inflammation. (B) Airway remodelling was determined by quantification of goblet cell hyperplasia, subepithelial collagen deposition and smooth muscle thickening. Data points represent means ± SEM of n = 6–8 animals per group.</p
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