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Departments of
*
Medicine and
Mechanical Engineering, University of Alberta, Edmonton, Alberta, Canada;
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
-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
-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
-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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