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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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Related in: MedlinePlus

Relative expression of mRNA for TOM1. qRT-PCR confirmation of upregulation of TOM1 in airway wall tissue of animals that received 6 weeks of chronic challenge and treatment with ant-miR-126. Significant difference compared to naïve controls is shown as ** (p < 0.01), compared to mice treated with ant-scrambled is shown as ## (p < 0.01).
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Figure 3: Relative expression of mRNA for TOM1. qRT-PCR confirmation of upregulation of TOM1 in airway wall tissue of animals that received 6 weeks of chronic challenge and treatment with ant-miR-126. Significant difference compared to naïve controls is shown as ** (p < 0.01), compared to mice treated with ant-scrambled is shown as ## (p < 0.01).

Mentions: To verify that delivery of ant-miR-126 was effective, we assessed the expression of TOM1 (target of Myb1) which is a negative regulator of IL-1β and TNF-α -induced signalling pathways. TOM1 has been defined as a target of miR-126 and is downregulated by it [17]. While there was no change in the expression of TOM1 in animals treated with ant-scrambled when compared to naïve mice, TOM1 was markedly and significantly upregulated in animals treated with ant-miR-126 (Figure 3). Whether TOM1 has any function in this model is unknown; however, this finding confirmed that ant-miR-126 was biologically active in the airway wall of these animals. Because samples from the antagomir-treated animals were processed for assessment of expression of mRNA, not miRNA, we were unable to directly confirm the effects of treatment with antagomirs on the levels of miR-126.


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)

Relative expression of mRNA for TOM1. qRT-PCR confirmation of upregulation of TOM1 in airway wall tissue of animals that received 6 weeks of chronic challenge and treatment with ant-miR-126. Significant difference compared to naïve controls is shown as ** (p < 0.01), compared to mice treated with ant-scrambled is shown as ## (p < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Relative expression of mRNA for TOM1. qRT-PCR confirmation of upregulation of TOM1 in airway wall tissue of animals that received 6 weeks of chronic challenge and treatment with ant-miR-126. Significant difference compared to naïve controls is shown as ** (p < 0.01), compared to mice treated with ant-scrambled is shown as ## (p < 0.01).
Mentions: To verify that delivery of ant-miR-126 was effective, we assessed the expression of TOM1 (target of Myb1) which is a negative regulator of IL-1β and TNF-α -induced signalling pathways. TOM1 has been defined as a target of miR-126 and is downregulated by it [17]. While there was no change in the expression of TOM1 in animals treated with ant-scrambled when compared to naïve mice, TOM1 was markedly and significantly upregulated in animals treated with ant-miR-126 (Figure 3). Whether TOM1 has any function in this model is unknown; however, this finding confirmed that ant-miR-126 was biologically active in the airway wall of these animals. Because samples from the antagomir-treated animals were processed for assessment of expression of mRNA, not miRNA, we were unable to directly confirm the effects of treatment with antagomirs on the levels of miR-126.

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