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.

Abstract

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 SCF 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.

• Authors: S Finotto, M Buerke, K Lingnau, E Schmitt, P R Galle, M F Neurath
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 107 Issue 2 Pg. 279-86 (Feb 2001) ISSN: 0091-6749 [Print] United States
• PMID: 11174194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Oligonucleotides, Antisense
• Stem Cell Factor
• Thionucleotides
• Interleukin-4
• Ovalbumin

Topics

• 3T3 Cells
• Administration, Topical
• Allergens (immunology)
• Animals
• Asthma (immunology, metabolism, physiopathology)
• Bronchoalveolar Lavage Fluid (cytology)
• Disease Models, Animal
• Eosinophils (cytology, drug effects)
• Fibroblasts (metabolism)
• Inflammation (prevention & control)
• Interleukin-4 (biosynthesis)
• Keratinocytes (metabolism)
• Leukocyte Count
• Lung Diseases (prevention & control)
• Mice
• Oligonucleotides, Antisense (administration & dosage)
• Ovalbumin (immunology)
• Stem Cell Factor (antagonists & inhibitors, drug effects, pharmacology)
• Thionucleotides (administration & dosage)