Aerosolized Syk antisense suppresses Syk expression, mediator release frommacrophages, and pulmonary inflammation

Syk protein tyrosine kinase (PTK) is involved in signaling in leukocytes, I n macrophages, Fc gamma-receptor cross-linking induces Syk PTK phosphorylat ion and activation, resulting in Syk-dependent events required for phagocyt osis and mediator release. We hypothesized that Syk antisense oligodeoxynuc leotides (ASO) delivered by aerosol to rat lungs in vivo would depress Syk PTK expression, mediator release from alveolar macrophages, and Syk-depende nt pulmonary inflammation. RT-PCR and RT-in situ PCR demonstrated that aero solized Syk ASO administration reduced Syk mRNA expression from alveolar ma crophages com pared with cells isolated from sham-treated rats. Western blo t analysis confirmed that Syk PTK expression was reduced after Syk ASO trea tment. Compared with sham-treated rats (scrambled oligodeoxynucleotide), Sy k ASO treatment suppressed Fc gamma-receptor-mediated nitric oxide (86.0 +/ - 8.3%) and TNF (73.1 +/- 3.1%) production by alveolar macrophages stimulat ed with IgG-anti-IgG complexes. In contrast, Fc gamma-receptor-induced IL-1 beta release was unaffected by Syk ASO treatment. Additionally, Syk ASO su ppressed Ag-induced pulmonary inflammation, suggesting that Syk ASO may pro ve useful as an anti-inflammatory therapy in disorders such as asthma.