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Inhibition of Allergic Inflammation in the Airways Using Aerosolized Antisense to Syk Kinase¹

Grant R. Stenton^2,*, Marina Ulanova^2,*, René E. Déry^*, Shaheed Merani^*, Moo-Kyung Kim^¶, Mark Gilchrist^*, Lakshmi Puttagunta, Sorin Musat-Marcu, Deborah James, Alan D. Schreiber^¶ and A. Dean Befus^3,*

Departments of ^* Medicine, Laboratory Medicine and Pathology, and Pharmacy, University of Alberta, and HistoBest Inc., Edmonton, Alberta, Canada; and ^¶ University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Activation of the protein tyrosine kinase Syk is an early event that follows cross-linking of FcR and FcR, 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 ₂ integrins, 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.

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