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Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target.

Collison A, Herbert C, Siegle JS, Mattes J, Foster PS, Kumar RK - BMC Pulm Med (2011)

Bottom Line: On the basis of the results obtained, animals were subsequently treated with either an antagomir to miR-126 (ant-miR-126) or a scrambled control antagomir once weekly during the 6 weeks of chronic challenge, and the effects on airway inflammation and remodelling were assessed using established morphometric techniques.The relative increase was maximal after 2 weeks of inhalational challenge and subsequently declined to baseline levels.Compared to treatment with the scrambled control, ant-miR-126 significantly reduced recruitment of intraepithelial eosinophils, but had no effect on the chronic inflammatory response, or on changes of airway remodelling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inflammation and Infection Research Centre, University of New South Wales, Sydney, Australia.

ABSTRACT

Background: The role of microRNAs (miRNAs) in regulating gene expression is currently an area of intense interest. Relatively little is known, however, about the role of miRNAs in inflammatory and immunologically-driven disorders. In a mouse model, we have previously shown that miRNAs are potentially important therapeutic targets in allergic asthma, because inhibition of miR-126, one of a small subset of miRNAs upregulated in the airway wall, effectively suppressed Th2-driven airway inflammation and other features of asthma. In the present study, we extended investigation of the therapeutic potential of miRNA inhibition to our well-established model of chronic asthma.

Methods: Female BALB/c mice were systemically sensitised with ovalbumin (OVA) and chronically challenged with low mass concentrations of aerosolised OVA for up to 6 weeks. Airway tissue was obtained by blunt dissection and RNA was isolated for miRNA profiling. On the basis of the results obtained, animals were subsequently treated with either an antagomir to miR-126 (ant-miR-126) or a scrambled control antagomir once weekly during the 6 weeks of chronic challenge, and the effects on airway inflammation and remodelling were assessed using established morphometric techniques.

Results: Compared to naïve mice, there was selective upregulation of a modest number of miRNAs, notably miR-126, in the airway wall tissue of chronically challenged animals. The relative increase was maximal after 2 weeks of inhalational challenge and subsequently declined to baseline levels. Compared to treatment with the scrambled control, ant-miR-126 significantly reduced recruitment of intraepithelial eosinophils, but had no effect on the chronic inflammatory response, or on changes of airway remodelling.

Conclusions: In this model of chronic asthma, there was an initial increase in expression of a small number of miRNAs in the airway wall, notably miR-126. However, this later declined to baseline levels, suggesting that sustained changes in miRNA may not be essential for perpetuation of chronic asthma. Moreover, inhibition of miR-126 by administration of an antagomir suppressed eosinophil recruitment into the airways but had no effect on chronic inflammation in the airway wall, or on changes of remodelling, suggesting that multiple miRNAs are likely to regulate the development of these lesions.

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Morphometric assessment of the effects of antagomir treatment. Quantification of (A) profile density of intraepithelial eosinophils (B) profile density of chronic inflammatory cells in the lamina propria (C) thickness of subepithelial collagenisation (all assessed in the trachea) and (D) grade of mucous cell change (assessed in intrapulmonary airways) after 6 weeks of chronic challenge and antagomir treatment. Values are expressed as mean ± SEM (A-C) or median ± interquartile range (D); 8 animals were assessed per group. Significant differences compared to naïve controls are shown as * (p < 0.05), ** (p < 0.01), *** (p < 0.001); significant difference compared to mice treated with ant-scrambled is shown as # (p < 0.05).
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Figure 2: Morphometric assessment of the effects of antagomir treatment. Quantification of (A) profile density of intraepithelial eosinophils (B) profile density of chronic inflammatory cells in the lamina propria (C) thickness of subepithelial collagenisation (all assessed in the trachea) and (D) grade of mucous cell change (assessed in intrapulmonary airways) after 6 weeks of chronic challenge and antagomir treatment. Values are expressed as mean ± SEM (A-C) or median ± interquartile range (D); 8 animals were assessed per group. Significant differences compared to naïve controls are shown as * (p < 0.05), ** (p < 0.01), *** (p < 0.001); significant difference compared to mice treated with ant-scrambled is shown as # (p < 0.05).

Mentions: Animals that were treated with the scrambled control antagomir developed airway wall changes that were indistinguishable from those observed in the chronic challenge model without any treatment [8], including recruitment of significant numbers of intraepithelial eosinophils, accumulation of chronic inflammatory cells in the lamina propria, subepithelial fibrosis and widespread goblet cell hyperplasia/metaplasia (Figure 2). Long-term administration of ant-miR-126 significantly reduced the numbers of intraepithelial eosinophils in the conducting airways (Figure 2A). However, treatment with ant-miR-126 had no effect on the chronic inflammatory response (Figure 2B). Similarly, changes of remodelling were essentially identical to those in mice treated with ant-scrambled (Figure 2C, D).


Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target.

Collison A, Herbert C, Siegle JS, Mattes J, Foster PS, Kumar RK - BMC Pulm Med (2011)

Morphometric assessment of the effects of antagomir treatment. Quantification of (A) profile density of intraepithelial eosinophils (B) profile density of chronic inflammatory cells in the lamina propria (C) thickness of subepithelial collagenisation (all assessed in the trachea) and (D) grade of mucous cell change (assessed in intrapulmonary airways) after 6 weeks of chronic challenge and antagomir treatment. Values are expressed as mean ± SEM (A-C) or median ± interquartile range (D); 8 animals were assessed per group. Significant differences compared to naïve controls are shown as * (p < 0.05), ** (p < 0.01), *** (p < 0.001); significant difference compared to mice treated with ant-scrambled is shown as # (p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3116478&req=5

Figure 2: Morphometric assessment of the effects of antagomir treatment. Quantification of (A) profile density of intraepithelial eosinophils (B) profile density of chronic inflammatory cells in the lamina propria (C) thickness of subepithelial collagenisation (all assessed in the trachea) and (D) grade of mucous cell change (assessed in intrapulmonary airways) after 6 weeks of chronic challenge and antagomir treatment. Values are expressed as mean ± SEM (A-C) or median ± interquartile range (D); 8 animals were assessed per group. Significant differences compared to naïve controls are shown as * (p < 0.05), ** (p < 0.01), *** (p < 0.001); significant difference compared to mice treated with ant-scrambled is shown as # (p < 0.05).
Mentions: Animals that were treated with the scrambled control antagomir developed airway wall changes that were indistinguishable from those observed in the chronic challenge model without any treatment [8], including recruitment of significant numbers of intraepithelial eosinophils, accumulation of chronic inflammatory cells in the lamina propria, subepithelial fibrosis and widespread goblet cell hyperplasia/metaplasia (Figure 2). Long-term administration of ant-miR-126 significantly reduced the numbers of intraepithelial eosinophils in the conducting airways (Figure 2A). However, treatment with ant-miR-126 had no effect on the chronic inflammatory response (Figure 2B). Similarly, changes of remodelling were essentially identical to those in mice treated with ant-scrambled (Figure 2C, D).

Bottom Line: On the basis of the results obtained, animals were subsequently treated with either an antagomir to miR-126 (ant-miR-126) or a scrambled control antagomir once weekly during the 6 weeks of chronic challenge, and the effects on airway inflammation and remodelling were assessed using established morphometric techniques.The relative increase was maximal after 2 weeks of inhalational challenge and subsequently declined to baseline levels.Compared to treatment with the scrambled control, ant-miR-126 significantly reduced recruitment of intraepithelial eosinophils, but had no effect on the chronic inflammatory response, or on changes of airway remodelling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inflammation and Infection Research Centre, University of New South Wales, Sydney, Australia.

ABSTRACT

Background: The role of microRNAs (miRNAs) in regulating gene expression is currently an area of intense interest. Relatively little is known, however, about the role of miRNAs in inflammatory and immunologically-driven disorders. In a mouse model, we have previously shown that miRNAs are potentially important therapeutic targets in allergic asthma, because inhibition of miR-126, one of a small subset of miRNAs upregulated in the airway wall, effectively suppressed Th2-driven airway inflammation and other features of asthma. In the present study, we extended investigation of the therapeutic potential of miRNA inhibition to our well-established model of chronic asthma.

Methods: Female BALB/c mice were systemically sensitised with ovalbumin (OVA) and chronically challenged with low mass concentrations of aerosolised OVA for up to 6 weeks. Airway tissue was obtained by blunt dissection and RNA was isolated for miRNA profiling. On the basis of the results obtained, animals were subsequently treated with either an antagomir to miR-126 (ant-miR-126) or a scrambled control antagomir once weekly during the 6 weeks of chronic challenge, and the effects on airway inflammation and remodelling were assessed using established morphometric techniques.

Results: Compared to naïve mice, there was selective upregulation of a modest number of miRNAs, notably miR-126, in the airway wall tissue of chronically challenged animals. The relative increase was maximal after 2 weeks of inhalational challenge and subsequently declined to baseline levels. Compared to treatment with the scrambled control, ant-miR-126 significantly reduced recruitment of intraepithelial eosinophils, but had no effect on the chronic inflammatory response, or on changes of airway remodelling.

Conclusions: In this model of chronic asthma, there was an initial increase in expression of a small number of miRNAs in the airway wall, notably miR-126. However, this later declined to baseline levels, suggesting that sustained changes in miRNA may not be essential for perpetuation of chronic asthma. Moreover, inhibition of miR-126 by administration of an antagomir suppressed eosinophil recruitment into the airways but had no effect on chronic inflammation in the airway wall, or on changes of remodelling, suggesting that multiple miRNAs are likely to regulate the development of these lesions.

Show MeSH
Related in: MedlinePlus