Aerosolized Syk antisense suppresses Syk expression, mediator release from macrophages, and pulmonary inflammation.
Syk protein tyrosine kinase (PTK) is involved in signaling in leukocytes. In macrophages, Fcgamma-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 Fcgamma-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, Fcgamma-receptor-induced IL-1beta 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.
Stenton
G R
GR
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Kim
M K
MK
Nohara
O
O
Chen
C F
CF
Hirji
N
N
Wills
F L
FL
Gilchrist
M
M
Hwang
P H
PH
Park
J G
JG
Finlay
W
W
Jones
R L
RL
Befus
A D
AD
Schreiber
A D
AD
D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count / Q000187:drug effects; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017452:Receptors, IgG / Q000502:physiology; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000336:Aerosols; D004792:Enzyme Precursors; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat