Effect of GSK-3.BETA. inhibitor TDZD-8 on activation of NF-kB during lung ischemia-reperfusion in rats

Abstract

Objective To investigate the effect of GSK-3β inhibitor TDZD-8 on activation of NF-kB during lung ischemia-repeffusion （I/R） in rats. Methods Thirty-two healthy male Sprague-Dawley rats, aged 8-10 weeks, weighing 250-280 g, were randomly divided into 4 groups （n = 8 each）： sham operation group （sham group） ; I/R group, I/R ＋ dimethyl sulfoxide （DMSO） group and I/R ＋ TDZD-8 group. Lung I/R was induced by clamping the left hilum of lung for 1 h followed by 2 h reperfusion. 10% DMSO and TDZD-8 1 mg/kg were inject- ed intravenously at 5 min before reperfusion in groups I/R ＋ DMSO and I/R ＋ TDZD-8, respectively. Blood sam- ples were taken at 2 h of repeffusion for determination of arterial partial pressure of oxygen （PaO2） and concentra- tions of plasma interleukin-6 （IL-6） and tumor necrosis factor-a （TNF-a） . The animals were then sacrificed and the left lung was removed for determination of W/D lung weight ratio, myeloperpxidase （MPO） activity, expression of phosphorylated glycogen synthase kinase-3 beta （p-GSK-313） and phosphorylated nuclear factor-kappa B p65 （p- NF-kB p65） and for microscopic examination. Results Compared with sham group, PaO2 and the expression of p- GSK-3β were significantly decreased, and the concentrations of plasma IL-6 and TNF-a, W/D lung weight ratio, MPO activity and expression of p-NF-kB p65 were significantly increased in the other groups （P 〈 0.05）, and PaO2 and the expression of p-GSK-3β were significantly increased and the other Parameters were significantly de- creased in I/R ＋ TDZD-8 group （P 〈 0.05）. There were no significant differences in the parameters mentioned above among groups I/Rand I/R ＋ DMSO （ P 〉 0.05）. Microscopic examination showed that I/R-induced lung in- jury was ameliorated by TDZD-8.Conclusion GSK-3β inhibitor TDZD-8 can attenuate lung I/R injury by down- regulating phosphorylation of NF-kB p65 and inhibiting inflammatory response. Key words: Protein-serine-threonine kinases; Reperfusion injury; Lung; NF-kappa B