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Molecular Medicine

, Volume 18, Issue 6, pp 948–956 | Cite as

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

  • Gabriela A Kulp
  • Ronald G. Tilton
  • David N Herndon
  • Marc G Jeschke
Research Article

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.

Notes

Acknowledgments

This work was supported by grants 8640 and 8660 from the Shriners of North America; grants GM RO1 GM087285-01, GM87285-01A2 and T32 GM08256-07, from the National Institutes of Health (NIH); Canadian Institutes of Health Research no. 123336; CFI Leader’s Opportunity Fund project no. 25407; NIH and Physicians’ Services Incorporated Foundation—health research grant program.

The authors would like to thank Robert Kraft, Ahmed Al-Mousawi and Mary Kelly for help with animal experiments and Maricella Pantoja for technical assistance in running the assays.

Supplementary material

10020_2012_1806948_MOESM1_ESM.pdf (1.2 mb)
Hyperglycemia Exacerbates Burn-Induced Liver Inflammation via Noncanonical Nuclear Factor-κB Pathway Activation

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Authors and Affiliations

  • Gabriela A Kulp
    • 1
    • 2
  • Ronald G. Tilton
    • 1
    • 3
    • 4
  • David N Herndon
    • 5
  • Marc G Jeschke
    • 6
  1. 1.Department of Ophthalmology and Visual SciencesUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Department of Biochemistry and Molecular Biology Graduate ProgramUniversity of Texas Medical BranchGalvestonUSA
  3. 3.Department of Internal MedicineUniversity of Texas Medical BranchGalvestonUSA
  4. 4.Sealy Center for Molecular MedicineUniversity of Texas Medical BranchGalvestonUSA
  5. 5.Shriners Hospital for Children and Department of SurgeryUniversity of Texas Medical BranchGalvestonUSA
  6. 6.Ross Tilley Burn Centre, Sunnybrook Health Science Centre, Sunnybrook Research Institute, Department of Surgery, Division of Plastic Surgery, Department of ImmunologyUniversity of TorontoTorontoCanada

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