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The Journal of Immunology, 2000, 164: 3790-3797.
Copyright © 2000 by The American Association of Immunologists

Aerosolized Syk Antisense Suppresses Syk Expression, Mediator Release from Macrophages, and Pulmonary Inflammation1

Grant R. Stenton*, Moo-Kyung Kim{ddagger}, Osamu Nohara*, Chin-Fu Chen{ddagger}, Nadir Hirji*, Fiona L. Wills*, Mark Gilchrist*, Pyoung-Han Hwang§, Jong-Gu Park, Warren Finlay{dagger}, Richard L. Jones*, A. Dean Befus2,* and Alan D. Schreiber{ddagger}

Departments of * Medicine and {dagger} Mechanical Engineering, University of Alberta, Edmonton, Alberta, Canada; {ddagger} University of Pennsylvania School of Medicine, Philadelphia, PA 19104; § Department of Pediatrics, Chonbuk National University, Chonju, Chonbuk, Korea; and Institute for Medical Sciences, Dongsan Medical Centre, Taegu, Korea

Syk protein tyrosine kinase (PTK) is involved in signaling in leukocytes. In macrophages, Fc{gamma}-receptor cross-linking induces Syk PTK phosphorylation and activation, resulting in Syk-dependent events required for phagocytosis and mediator release. We hypothesized that Syk antisense oligodeoxynucleotides (ASO) delivered by aerosol to rat lungs in vivo would depress Syk PTK expression, mediator release from alveolar macrophages, and Syk-dependent pulmonary inflammation. RT-PCR and RT-in situ PCR demonstrated that aerosolized Syk ASO administration reduced Syk mRNA expression from alveolar macrophages compared with cells isolated from sham-treated rats. Western blot analysis confirmed that Syk PTK expression was reduced after Syk ASO treatment. Compared with sham-treated rats (scrambled oligodeoxynucleotide), Syk ASO treatment suppressed Fc{gamma}-receptor-mediated nitric oxide (86.0 ± 8.3%) and TNF (73.1 ± 3.1%) production by alveolar macrophages stimulated with IgG-anti-IgG complexes. In contrast, Fc{gamma}-receptor-induced IL-1ß release was unaffected by Syk ASO treatment. Additionally, Syk ASO suppressed Ag-induced pulmonary inflammation, suggesting that Syk ASO may prove useful as an anti-inflammatory therapy in disorders such as asthma.







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