Inhibition of allergic inflammation in the airways using aerosolized antisense to Syk kinase.
Activation of the protein tyrosine kinase Syk is an early event that follows cross-linking of Fc gamma R and Fc epsilon R, leading to the release of biologically active molecules in inflammation. We reported previously that aerosolized Syk antisense oligodeoxynucleotides (ASO) depresses Syk expression in inflammatory cells, the release of mediators from alveolar macrophages, and pulmonary inflammation. To study the effect of Syk ASO in allergic inflammation and airway hyperresponsiveness, we used the Brown Norway rat model of OVA-induced allergic asthma. Syk ASO, delivered in a liposome, carrier/lipid complex by aerosol to rats, significantly inhibited the Ag-induced inflammatory cell infiltrate in the bronchoalveolar space, decreasing both neutrophilia and eosinophilia. The number of eosinophils in the lung parenchyma was also diminished. Syk ASO also depressed up-regulation of the expression of beta(2) integrins, alpha(4) integrin, and ICAM-1 in bronchoalveolar lavage leukocytes and reversed the Ag-induced decrease in CD62L expression on neutrophils. Furthermore, the increase in TNF levels in bronchoalveolar lavage following Ag challenge was significantly inhibited. Syk ASO also suppressed Ag-mediated contraction of the trachea in a complementary model. Thus, aerosolized Syk ASO suppresses many of the central components of allergic asthma and inflammation and may provide a new therapeutic approach.
Stenton
Grant R
GR
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Ulanova
Marina
M
Déry
René E
RE
Merani
Shaheed
S
Kim
Moo-Kyung
MK
Gilchrist
Mark
M
Puttagunta
Lakshmi
L
Musat-Marcu
Sorin
S
James
Deborah
D
Schreiber
Alan D
AD
Befus
A Dean
AD
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D066298:In Vitro Techniques; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000276:immunology; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage*; D010047:Ovalbumin / Q000008:administration & dosage / Q000494:pharmacology; D010477:Perfusion; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D000072377:Syk Kinase; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D000336:Aerosols; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat