Local administration of antisense phosphorothioate oligonucleotides to the c-kit ligand, stem cell factor, suppresses airway inflammation and IL-4 production in a murine model of asthma

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:107

Article

Finotto, S ; Buerke, M ; Lingnau, K ; Schmitt, E ; Galle, PR ; Neurath, MF

关键词: stem cell factor;    mast cells;    antisense DNA;    asthma;    T(H)2 cytokines;   

DOI  :  10.1067/mai.2001.113049

来源: Elsevier

【 摘 要 】

Background: The c-kit ligand, stem cell factor (SCF), is an important activating and chemotactic factor for both mast cells and eosinophils, These cells are known to play a fundamental role in the pathogenesis of asthma. Objective: Our goal was to analyze the functional role of SCF in the pathogenesis of asthma. Methods: The expression of SCF was targeted in fibroblasts, epithelial cells, and locally in a murine model of asthma in mice induced by ovalbumin sensitization with an antisense DNA strategy. Results: We could suppress SCF expression in NIH 3T3 fibroblasts and SP1 epithelial cells by a specific antisense phosphorothioate oligonucleotide overlapping the translation start site of SCF, whereas control oligonucleotides were virtually inactive. We then focused on the role of SCF in a murine model of asthma associated with late-phase allergic inflammation in ovalbumin-sensitized mice: Local intranasal administration of FITC-labeled SCF antisense oligonucleotides led to strong DNA uptake in interstitial lung cells associated with a striking reduction of intracellular SCF expression. Such intrapulmonary blockade of SCF expression after repeated allergen challenges suppressed various signs of lung inflammation including IL-4 production and infiltration of eosinophils. SCF antisense DNA treatment was at least as effective as corticosteroid treatment. Conclusion: These data indicate a critical role for SCP in a murine asthma model and suggest that local delivery of SCF antisense oligonucleotides may be a novel approach for the treatment of inflammatory lung disorders such as asthma.

【 授权许可】

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