Hyperglycemia Exacerbates Burn-Induced Liver Inflammation via Noncanonical Nuclear Factor-κB Pathway Activation

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.

Animal models in burn research

“…Another consideration relates to the need to have a burn injury model of sufficient magnitude to cause hypermetabolism observed in human burns with high TBSA. During the early post-burn phase in humans, hyperglycemia occurs as a result of an increased rate of glucose appearance along with an impaired tissue extraction of glucose, leading to an overall increase of glucose and lactate [67]. Therefore, while the rat burn model is superior to the mouse in its ability to recapture hypermetabolism, it becomes complex when one tries to incorporate an infection feature to this model to replicate the post-burn sepsis seen in patients with greater than 60% TBSA.…”

Alcohol Modulation of the Postburn Hepatic Response

“…The subsequent hyperglycemia is associated with increased mortality and infectious complications in pediatric burn patients [34] and a prospective analysis of 152 burn patients demonstrated found decreased rates of pneumonia, ventilator-associated pneumonia, and urinary tract infection infections with tight glycemic control [35]. Hyperglycemia also aggravates burn-induced liver inflammation via activating nuclear factor-κB (NF-κB) signaling in hepatocytes as demonstrated in a rat model [36]. Alcohol consumption can have paradoxical effects on plasma glucose levels depending on the setting.…”

Nutrition and Anabolic Pharmacotherapies in the Care of Burn Patients

“…During the early phase of postthermal injury, patients experience hyperglycemia as a result of the catabolic state and hormonal environment that favors glucose appearance along with impaired glucose extraction by tissues 72 , 73 . This hyperglycemic state following burn injury can be detrimental and can lead to adverse outcomes in these patients if not controlled and resolved swiftly 38 , 74 , 75 . Studies have shown that burn patients with poor glucose control experience a significantly higher incidence of infections and mortality compared with burn patients with good glucose control 39 , 74 , 75 .…”

“…Following this primary goal, nutrition support is used to alleviate and modulate the postburn catabolic and pathological responses of hypermetabolism, immunosuppression, and disturbed wound healing. Despite the obvious need for nutrition support in these patients, the supply of excess nutrition in the form of carbohydrates and fat can result in hyperglycemia and fat infiltration of organs 37 – 39 . Currently, no standardized nutrition support guidelines exist for burn patients.…”

“…Despite the obvious need for nutrition support in these patients, the supply of excess nutrition in the form of carbohydrates and fat can result in hyperglycemia and fat infiltration of organs. [37][38][39] Currently, no standardized nutrition support guidelines exist for burn patients. There are only recommendations, [40][41][42] and we at the Ross Tilley Burn Center recommend the use of high carbohydrate/high glucose, high protein/amino acid intake, and a low-fat diet with emphasis on unsaturated fatty acids to attenuate the catabolic and pathological mechanisms following burn (Table 1).…”