Abstract
Hyperglycemia and inflammation are hallmarks of burn injury. In this study, we used a rat model of hyperglycemia and burn injury to investigate the effects of hyperglycemia on inflammatory responses in the liver. Hyperglycemia was induced in male Sprague-Dawley rats with streptozotocin (STZ) (35-40 mg/kg), followed by a 60% third-degree scald burn injury. Cytokine levels (by multiplex, in cytosolic liver extracts), hormones (by enzyme-linked immunosorbent assay [ELISA], in serum), nuclear factor (NF)-κB protein deoxyribonucleic acid (DNA) binding (by ELISA, in nuclear liver extracts) and liver functional panel (using VetScan, in serum) were measured at different time points up to 7 d after burn injury. Blood glucose significantly increased after burn injury in both groups with different temporal patterns. Hyperglycemic rats were capable of endogenous insulin secretion, which was enhanced significantly versus controls 12 h after burn injury. DNA binding data of liver nuclear extracts showed a robust and significant activation of the noncanonical NF-κB pathway in the hyperglycemic versus control burn animals, including increased NF-κB-inducing kinase expression (p < 0.05). Liver acute-phase proteins and cytokine expression were increased, whereas secretion of constitutive proteins was decreased after burn injury in hyperglycemic versus control animals (p < 0.05). These results indicate that burn injury to the skin rapidly activated canonical and noncanonical NF-κB pathways in the liver. Robust activation of the NF-κB noncanonical pathway was associated with increased expression of inflammatory markers and acute-phase proteins, and impaired glucose metabolism. Hyperglycemia is detrimental to burn outcome by augmenting inflammation mediated by hepatic noncanonical NF-κB pathway activation.
Highlights
IntroductionHyperglycemia occurs in critically ill patients (transplant, surgical, trauma, burns) and has been associated with adverse clinical outcomes [1]
Hyperglycemia occurs in critically ill patients and has been associated with adverse clinical outcomes [1]
In clinical [5] and animal [43] studies, we showed that insulin administration has antiinflammatory effects in burned patients and decreases resting energy expenditure
Summary
Hyperglycemia occurs in critically ill patients (transplant, surgical, trauma, burns) and has been associated with adverse clinical outcomes [1]. Tight euglycemic control in these patient populations has been shown to be beneficial, with decreased incidence of infection, decreased acute hospital stay and decreased morbidity and mortality [1]. Ill patients with hyperglycemia have a higher incidence of infection and sepsis, both in the adult population (18–55 years old) and in children [2,3]. In patients with extensive burn injury, control of hyperglycemia is associated with better graft survival and a decrease in resting energy expenditure [4,5]. Hyperglycemia has been associated with significant risk for wound infection, pneumonia and bacteremia in burn injury patients [6]. Massive release of cytokines in systemic circulation after burn injury can lead to distant organ damage [10]
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