We tested the hypothesis that glycogen synthase kinase 3α/β (GSK3α/β) modulates tumor necrosis factor-a (TNF) induced increased lung vascular permeability. Rats were treated with TNF (i.v., ~100 ng/ml) or vehicle 0.5 h, 4.0 h and 24.0 h prior to lung isolation. Rats were co-treated with the GSK3α/β inhibitors SB216763 (0.6 mg/kg) or TDZD-8 (1.0 mg/kg). After TNF, the isolated lung was assessed for hemodynamics, wet-dry/dry weight (W-D/D) and extravascular albumin. Extravascular albumin significantly increased at TNF-24 h compared to Control. In the GSK3α/β-inhibited +TNF groups, extravascular albumin was similar to the Control and respective SB216763 and TDZD-8 groups. In separate studies, to assess GSK3α/β-activity, lung lysate was assessed for phospho-GSK3α/β-Ser21/9, total GSK3α/β, un-phospho-β-catenin-Ser33/37and total β-catenin. In the TNF-4.0 h group, there was no change in GSK3α/phospho-GSK3α-Ser21 but there was an increase in GSK3β/GSK3β-Ser9 compared to Control, indicating GSK3β activation at TNF-4.0 h. GSK3β activation was verified because there was a decrease in un-phospho-β-catenin-Ser33/37/β-catenin in the TNF- 4.0 group, a specific outcome for GSK3β activation. In the SB216763+TNF group, un-phospho-β-catenin-Ser33/37 was similar to Control, indicating prevention of TNF-induced GSK3β activation. In the TNF-24 h group, there were increases in the biomarkers of inflammation phospho-eNOS-Ser 1117 and oxidized protein, which did not occur in the SB216763+TNF-24 h and TDZD-8+TNF-24 h groups. In the SB216763+TNF-24 h and TDZD-8+TNF-24 h groups, un-phospho-β-catenin-Ser33/37 was greater than in the Control, indicating continued inhibition of GSK3β. The data indicates that pharmacologic inhibition of GSK3β inhibits TNF induced increased endothelial permeability associated with lung inflammation.
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