(734) - Hyperglycemia Exacerbates Ischemia-Reperfusion Injury of the Lung By Activating TLR4 Signaling Pathway

Abstract

PurposeAcute hyperglycemia enhances oxidative stress in heart and kidney through activation of Toll-like receptor 4 (TLR4) signaling, which is a key genetic pathway that determines the susceptibility to acute lung injury, including infections and ischemia-reperfusion injury (IRI). It is suggested that the hyperglycemia-induced oxidative stress regulates TLR4 signaling in the lung as well. Direct evidence, however, is quite limited. The purpose of the study was to investigate the TLR4 signaling in acute lung injury under high-glucose conditions.MethodsC57BL/6Ncr wild-type mice were divided into following three groups: sham, ischemia-reperfusion injury in normoglycemia (NG), and ischemia-reperfusion injury in hyperglycemia (HG). Acute hyperglycemia in the HG group was established via intraperitoneal injection of 0.3 ml of 10% glucose (mean glucose level: 317 ± 84 mg/dl in the HG group, 132 ± 32 mg/dl in the NG group). In the NG and HG group, mice underwent 1 h of ischemia and 2 h of reperfusion in the left lung via hilar occlusion. Mice in the sham group underwent 2 h of perfusion without ischemia.ResultsHyperglycemia significantly exacerbated pulmonary compliance and vascular permeability of the left lung after ischemia-reperfusion (p < 0.05). In addition, TLR4 signaling and inflammatory cytokine (IL-6) expressions were up-regulated in the HG group compared to those in the NG group (p < 0.05, Figure). Pharmacological blocking of TLR4 signaling attenuated vascular permeability of the left lung and IL-6 expressions in the NG and HG group (p < 0.05, Figure).ConclusionThese data support that hyperglycemia up-regulates oxidative stress via TLR4 signaling pathway in IRI of the lung. Pharmacological inhibition of TLR4 pathway may help reducing oxidative responses under hyperglycemic conditions. PurposeAcute hyperglycemia enhances oxidative stress in heart and kidney through activation of Toll-like receptor 4 (TLR4) signaling, which is a key genetic pathway that determines the susceptibility to acute lung injury, including infections and ischemia-reperfusion injury (IRI). It is suggested that the hyperglycemia-induced oxidative stress regulates TLR4 signaling in the lung as well. Direct evidence, however, is quite limited. The purpose of the study was to investigate the TLR4 signaling in acute lung injury under high-glucose conditions. Acute hyperglycemia enhances oxidative stress in heart and kidney through activation of Toll-like receptor 4 (TLR4) signaling, which is a key genetic pathway that determines the susceptibility to acute lung injury, including infections and ischemia-reperfusion injury (IRI). It is suggested that the hyperglycemia-induced oxidative stress regulates TLR4 signaling in the lung as well. Direct evidence, however, is quite limited. The purpose of the study was to investigate the TLR4 signaling in acute lung injury under high-glucose conditions. MethodsC57BL/6Ncr wild-type mice were divided into following three groups: sham, ischemia-reperfusion injury in normoglycemia (NG), and ischemia-reperfusion injury in hyperglycemia (HG). Acute hyperglycemia in the HG group was established via intraperitoneal injection of 0.3 ml of 10% glucose (mean glucose level: 317 ± 84 mg/dl in the HG group, 132 ± 32 mg/dl in the NG group). In the NG and HG group, mice underwent 1 h of ischemia and 2 h of reperfusion in the left lung via hilar occlusion. Mice in the sham group underwent 2 h of perfusion without ischemia. C57BL/6Ncr wild-type mice were divided into following three groups: sham, ischemia-reperfusion injury in normoglycemia (NG), and ischemia-reperfusion injury in hyperglycemia (HG). Acute hyperglycemia in the HG group was established via intraperitoneal injection of 0.3 ml of 10% glucose (mean glucose level: 317 ± 84 mg/dl in the HG group, 132 ± 32 mg/dl in the NG group). In the NG and HG group, mice underwent 1 h of ischemia and 2 h of reperfusion in the left lung via hilar occlusion. Mice in the sham group underwent 2 h of perfusion without ischemia. ResultsHyperglycemia significantly exacerbated pulmonary compliance and vascular permeability of the left lung after ischemia-reperfusion (p < 0.05). In addition, TLR4 signaling and inflammatory cytokine (IL-6) expressions were up-regulated in the HG group compared to those in the NG group (p < 0.05, Figure). Pharmacological blocking of TLR4 signaling attenuated vascular permeability of the left lung and IL-6 expressions in the NG and HG group (p < 0.05, Figure). Hyperglycemia significantly exacerbated pulmonary compliance and vascular permeability of the left lung after ischemia-reperfusion (p < 0.05). In addition, TLR4 signaling and inflammatory cytokine (IL-6) expressions were up-regulated in the HG group compared to those in the NG group (p < 0.05, Figure). Pharmacological blocking of TLR4 signaling attenuated vascular permeability of the left lung and IL-6 expressions in the NG and HG group (p < 0.05, Figure). ConclusionThese data support that hyperglycemia up-regulates oxidative stress via TLR4 signaling pathway in IRI of the lung. Pharmacological inhibition of TLR4 pathway may help reducing oxidative responses under hyperglycemic conditions. These data support that hyperglycemia up-regulates oxidative stress via TLR4 signaling pathway in IRI of the lung. Pharmacological inhibition of TLR4 pathway may help reducing oxidative responses under hyperglycemic conditions.