W Guo1, D Ge, Q Wang, S Xu, L Xue, C Lu, L Tan. 1. Department of Thoracic Surgery, The Affiliated Zhongshan Hospital of Fudan University, Xuhui District, Shanghai, China.
Abstract
BACKGROUND: Ischemia-reperfusion injury (IRI) is a significant factor contributing to primary graft failure in lung transplantation. Given a pivotal role of mitochondria in IRI-related molecular events, the effects of diazoxide, a selective opener of mitochondrial adenosine-5'-triphosphate (ATP)-sensitive potassium channels (mitoK(ATP)), on IRI were investigated in a rat model of lung transplantation. METHODS: The 108 rats were randomly assigned to 5 groups; a sham-operated, 2 control, and 2 experimental groups that received either diazoxide alone or a combination of diazoxide with 5-hydroxydecanoate sodium salt. Lung injuries were assessed by multiple parameters at 2 hours or 24 hours after reperfusion, including oxygenation index, wet/dry weight ratio of transplanted lungs, lung morphology, as well as measurements of myeloperoxidase, malondialdehyde, total antioxidant capacity, tumor necrosis factor-α, and interleukin-6. RESULTS: Compared with the sham group, the 2 control groups revealed significant changes among most parameters of lung injury measured at either 2 hours or 24 hours after reperfusion. The extent of the changes was dramatically reduced by the administration of diazoxide. Importantly, the protective effect of diazoxide was almost completely reversed by co-administration of 5-hydroxydecanoate sodium salt, a selective blocker of mitoK(ATP). CONCLUSIONS: These data provide evidence for substantial protective effects of diazoxide in an in vivo rat lung IRI model. Pharmacological modulation of mitoK(ATP) may be a potential strategy to reduce IRI-induced primary graft failure in lung transplantation.
BACKGROUND:Ischemia-reperfusion injury (IRI) is a significant factor contributing to primary graft failure in lung transplantation. Given a pivotal role of mitochondria in IRI-related molecular events, the effects of diazoxide, a selective opener of mitochondrial adenosine-5'-triphosphate (ATP)-sensitive potassium channels (mitoK(ATP)), on IRI were investigated in a rat model of lung transplantation. METHODS: The 108 rats were randomly assigned to 5 groups; a sham-operated, 2 control, and 2 experimental groups that received either diazoxide alone or a combination of diazoxide with 5-hydroxydecanoate sodium salt. Lung injuries were assessed by multiple parameters at 2 hours or 24 hours after reperfusion, including oxygenation index, wet/dry weight ratio of transplanted lungs, lung morphology, as well as measurements of myeloperoxidase, malondialdehyde, total antioxidant capacity, tumor necrosis factor-α, and interleukin-6. RESULTS: Compared with the sham group, the 2 control groups revealed significant changes among most parameters of lung injury measured at either 2 hours or 24 hours after reperfusion. The extent of the changes was dramatically reduced by the administration of diazoxide. Importantly, the protective effect of diazoxide was almost completely reversed by co-administration of 5-hydroxydecanoate sodium salt, a selective blocker of mitoK(ATP). CONCLUSIONS: These data provide evidence for substantial protective effects of diazoxide in an in vivo rat lung IRI model. Pharmacological modulation of mitoK(ATP) may be a potential strategy to reduce IRI-induced primary graft failure in lung transplantation.