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.
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.


CONCLUSIONS
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.
Finotto
S
S
Laboratory of Immunology, Medical Clinic I, Medical Clinic II, and the Institute of Immunology, University of Mainz, Germany.
Buerke
M
M
Lingnau
K
K
Schmitt
E
E
Galle
P R
PR
Neurath
M F
MF
D016475:3T3 Cells; D000287:Administration, Topical; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D015847:Interleukin-4 / Q000096:biosynthesis*; D015603:Keratinocytes / Q000378:metabolism; D007958:Leukocyte Count; D008171:Lung Diseases / Q000517:prevention & control; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D010047:Ovalbumin / Q000276:immunology; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000494:pharmacology*; D013873:Thionucleotides / Q000008:administration & dosage
D000485:Allergens; D016376:Oligonucleotides, Antisense; D019089:Stem Cell Factor; D013873:Thionucleotides; D015847:Interleukin-4; D010047:Ovalbumin