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An intranasal selective antisense oligonucleotide impairs lung cyclooxygenase-2 production and improves inflammation, but worsens airway function, in house dust mite sensitive mice.

Torres R, Herrerias A, Serra-Pagès M, Roca-Ferrer J, Pujols L, Marco A, Picado C, de Mora F - Respir. Res. (2008)

Bottom Line: Finally, mRNA levels of hPGD synthase remained unchanged.Intranasal antisense therapy against COX-2 in vivo mimicked the reported impairment of COX-2 regulation in the airway cells of asthmatic patients.This strategy revealed an unexpected novel dual effect: inflammation was improved but AHR worsened.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pneumology and Respiratory Allergy, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain. rosa.torres@uab.cat

ABSTRACT

Background: Despite its reported pro-inflammatory activity, cyclooxygenase (COX)-2 has been proposed to play a protective role in asthma. Accordingly, COX-2 might be down-regulated in the airway cells of asthmatics. This, together with results of experiments to assess the impact of COX-2 blockade in ovalbumin (OVA)-sensitized mice in vivo, led us to propose a novel experimental approach using house dust mite (HDM)-sensitized mice in which we mimicked altered regulation of COX-2.

Methods: Allergic inflammation was induced in BALBc mice by intranasal exposure to HDM for 10 consecutive days. This model reproduces spontaneous exposure to aeroallergens by asthmatic patients. In order to impair, but not fully block, COX-2 production in the airways, some of the animals received an intranasal antisense oligonucleotide. Lung COX-2 expression and activity were measured along with bronchovascular inflammation, airway reactivity, and prostaglandin production.

Results: We observed impaired COX-2 mRNA and protein expression in the lung tissue of selective oligonucleotide-treated sensitized mice. This was accompanied by diminished production of mPGE synthase and PGE2 in the airways. In sensitized mice, the oligonucleotide induced increased airway hyperreactivity (AHR) to methacholine, but a substantially reduced bronchovascular inflammation. Finally, mRNA levels of hPGD synthase remained unchanged.

Conclusion: Intranasal antisense therapy against COX-2 in vivo mimicked the reported impairment of COX-2 regulation in the airway cells of asthmatic patients. This strategy revealed an unexpected novel dual effect: inflammation was improved but AHR worsened. This approach will provide insights into the differential regulation of inflammation and lung function in asthma, and will help identify pharmacological targets within the COX-2/PG system.

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Related in: MedlinePlus

Airway inflammation in non-sensitized and in untreated or treated HDM-sensitized mice. Graph (a) shows the total inflammatory cell count in bronchoalveolar lavage fluid, and graph (b) depicts the eosinophils infiltrating the airways in the same animals. In both cases, the selective COX-2 antisense oligonucleotide caused a significant reduction in the accumulation of inflammatory cells in the lungs. No differences were found between the untreated and the control mismatched oligonucleotide-treated sensitized mice. Data are shown as means ± SEM (*p < 0.05, **p < 0.01). ASO: antisense oligonucleotide, MM: mismatched oligonucleotide (n = 12)
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Figure 5: Airway inflammation in non-sensitized and in untreated or treated HDM-sensitized mice. Graph (a) shows the total inflammatory cell count in bronchoalveolar lavage fluid, and graph (b) depicts the eosinophils infiltrating the airways in the same animals. In both cases, the selective COX-2 antisense oligonucleotide caused a significant reduction in the accumulation of inflammatory cells in the lungs. No differences were found between the untreated and the control mismatched oligonucleotide-treated sensitized mice. Data are shown as means ± SEM (*p < 0.05, **p < 0.01). ASO: antisense oligonucleotide, MM: mismatched oligonucleotide (n = 12)

Mentions: HDM-sensitized mice developed a clear peribronchial and perivascular eosinophilic inflammation (Figure 3e) with goblet cell hyperplasia, compared with the non-sensitized animals. No differences were found in the total number of inflammatory cells or in eosinophil accumulation between untreated and mismatched control oligonucleotide-treated sensitized animals (Figure 5a and 5b). In contrast, when COX-2 was selectively inhibited in sensitized mice, the level of inflammation was clearly and significantly reduced to 50%–55% of its value in the untreated HDM-sensitized mice, depending on whether total cells or eosinophils were considered (Figure 5a and 5b, respectively). This reduced inflammation was also visible in the lung sections (Figure 3f).


An intranasal selective antisense oligonucleotide impairs lung cyclooxygenase-2 production and improves inflammation, but worsens airway function, in house dust mite sensitive mice.

Torres R, Herrerias A, Serra-Pagès M, Roca-Ferrer J, Pujols L, Marco A, Picado C, de Mora F - Respir. Res. (2008)

Airway inflammation in non-sensitized and in untreated or treated HDM-sensitized mice. Graph (a) shows the total inflammatory cell count in bronchoalveolar lavage fluid, and graph (b) depicts the eosinophils infiltrating the airways in the same animals. In both cases, the selective COX-2 antisense oligonucleotide caused a significant reduction in the accumulation of inflammatory cells in the lungs. No differences were found between the untreated and the control mismatched oligonucleotide-treated sensitized mice. Data are shown as means ± SEM (*p < 0.05, **p < 0.01). ASO: antisense oligonucleotide, MM: mismatched oligonucleotide (n = 12)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2600823&req=5

Figure 5: Airway inflammation in non-sensitized and in untreated or treated HDM-sensitized mice. Graph (a) shows the total inflammatory cell count in bronchoalveolar lavage fluid, and graph (b) depicts the eosinophils infiltrating the airways in the same animals. In both cases, the selective COX-2 antisense oligonucleotide caused a significant reduction in the accumulation of inflammatory cells in the lungs. No differences were found between the untreated and the control mismatched oligonucleotide-treated sensitized mice. Data are shown as means ± SEM (*p < 0.05, **p < 0.01). ASO: antisense oligonucleotide, MM: mismatched oligonucleotide (n = 12)
Mentions: HDM-sensitized mice developed a clear peribronchial and perivascular eosinophilic inflammation (Figure 3e) with goblet cell hyperplasia, compared with the non-sensitized animals. No differences were found in the total number of inflammatory cells or in eosinophil accumulation between untreated and mismatched control oligonucleotide-treated sensitized animals (Figure 5a and 5b). In contrast, when COX-2 was selectively inhibited in sensitized mice, the level of inflammation was clearly and significantly reduced to 50%–55% of its value in the untreated HDM-sensitized mice, depending on whether total cells or eosinophils were considered (Figure 5a and 5b, respectively). This reduced inflammation was also visible in the lung sections (Figure 3f).

Bottom Line: Finally, mRNA levels of hPGD synthase remained unchanged.Intranasal antisense therapy against COX-2 in vivo mimicked the reported impairment of COX-2 regulation in the airway cells of asthmatic patients.This strategy revealed an unexpected novel dual effect: inflammation was improved but AHR worsened.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pneumology and Respiratory Allergy, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain. rosa.torres@uab.cat

ABSTRACT

Background: Despite its reported pro-inflammatory activity, cyclooxygenase (COX)-2 has been proposed to play a protective role in asthma. Accordingly, COX-2 might be down-regulated in the airway cells of asthmatics. This, together with results of experiments to assess the impact of COX-2 blockade in ovalbumin (OVA)-sensitized mice in vivo, led us to propose a novel experimental approach using house dust mite (HDM)-sensitized mice in which we mimicked altered regulation of COX-2.

Methods: Allergic inflammation was induced in BALBc mice by intranasal exposure to HDM for 10 consecutive days. This model reproduces spontaneous exposure to aeroallergens by asthmatic patients. In order to impair, but not fully block, COX-2 production in the airways, some of the animals received an intranasal antisense oligonucleotide. Lung COX-2 expression and activity were measured along with bronchovascular inflammation, airway reactivity, and prostaglandin production.

Results: We observed impaired COX-2 mRNA and protein expression in the lung tissue of selective oligonucleotide-treated sensitized mice. This was accompanied by diminished production of mPGE synthase and PGE2 in the airways. In sensitized mice, the oligonucleotide induced increased airway hyperreactivity (AHR) to methacholine, but a substantially reduced bronchovascular inflammation. Finally, mRNA levels of hPGD synthase remained unchanged.

Conclusion: Intranasal antisense therapy against COX-2 in vivo mimicked the reported impairment of COX-2 regulation in the airway cells of asthmatic patients. This strategy revealed an unexpected novel dual effect: inflammation was improved but AHR worsened. This approach will provide insights into the differential regulation of inflammation and lung function in asthma, and will help identify pharmacological targets within the COX-2/PG system.

Show MeSH
Related in: MedlinePlus