The role of the liver during the post-burn response is essentially unknown, and many burn and trauma surgeons consider the liver as unimportant, with little or no effect on post-burn outcomes. Others strongly suggest that intact liver function and integrity are essential for burn patients'recovery, because the liver modulates metabolic pathways, inflammatory processes, immune functions, and acute-phase responses. Our preliminary data indicate that a severe thermal injury causes hepatic damage and dysfunction by inducing hepatocyte endoplasmic reticulum stress (ER stress) and hepatocyte apoptosis. We hypothesize that hepatic ER stress and subsequent apoptosis contribute to adverse post-burn outcomes, and that attenuating hepatic ER stress and apoptosis will enhance hepatic function, which is associated with improved post-burn morbidity and mortality. The exact mechanisms by which a burn induces hepatic ER stress, apoptosis, and dysfunction are not known, limiting therapeutic intervention. In preliminary studies we found that these pathophysiological processes are related to hepatic inflammation, altered phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling, depletion of the hepatic calcium stores, the unfolded protein response (UPR), and mitochondrial dysfunction. We now propose to characterize the post-burn molecular and physiological changes that lead to hepatic apoptosis and dysfunction. Hypothesis 2 is that burn induces hepatic damage by altering the PI3K/Akt and inositol 1, 4, 5,-triphosphate receptor (IP3R) signaling pathways, leading to calcium store depletion, cytochrome c release, ER stress/UPR, and consequently to hepatocyte apoptosis.
In Aim 1 we will determine whether post-burn hepatocyte ER stress and apoptosis contribute to morbidity and mortality.
Aim 2 is to determine in vivo the cellular and sub-cellular mechanisms which cause post-burn alterations in hepatic intracellular calcium, ER stress and UPR, and hepatocyte apoptosis.
Aim 3 is designed to identify and characterize an intervention that will improve hepatic integrity and function post-burn and is readily available in the clinical setting. Based on our preliminary data we will use insulin, which attenuates hepatic damage and improves liver function post-burn. The mechanisms underlying these effects are not understood;we hypothesize that post-burn insulin administration improves hepatocyte viability and liver function via normalization of intracellular calcium and IP3R signaling pathways, attenuation of cytochrome c release, and reduction of ER stress/UPR, leading to markedly decreased hepatocyte apoptosis. We further hypothesize that insulin exerts its effects via insulin-specific signal transduction pathway activation. We will test this hypothesis by comparing the effects of insulin on hepatocyte ER stress/UPR and apoptosis to the effects of a glucose- lowering drug, as well as chemical ER chaperones on ER stress/UPR, apoptosis, and post-burn outcomes. Identifying and understanding the cellular and molecular mechanisms by which insulin or glucose modulation will improve outcomes could lead to the establishment of novel treatment options for severely burned patients.

Public Health Relevance

A key and novel aspect of this study is our hypothesis that hepatic apoptosis and ER stress play an important role in post-burn morbidity and mortality, and that insulin administration improves these adverse outcomes by decreasing hepatic apoptosis and ER stress. This study is important because characterizing and identifying the molecular mechanisms associated with burn-induced hepatic apoptosis and ER stress will lead to improvements in the clinical care of severely burned patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM087285-01A2
Application #
7898052
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2010-09-30
Project End
2014-08-31
Budget Start
2010-09-30
Budget End
2011-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$210,600
Indirect Cost
Name
Sunnybrook & Women's Coll Health Sciences Center
Department
Type
DUNS #
200466345
City
Toronto
State
ON
Country
Canada
Zip Code
M4 3-M5
Mason, Stephanie A; Nathens, Avery B; Byrne, James P et al. (2017) Trends in the epidemiology of major burn injury among hospitalized patients: A population-based analysis. J Trauma Acute Care Surg 83:867-874
Abdullahi, Abdikarim; Chen, Peter; Stanojcic, Mile et al. (2017) IL-6 Signal From the Bone Marrow is Required for the Browning of White Adipose Tissue Post Burn Injury. Shock 47:33-39
Jeschke, Marc G; Peck, Michael D (2017) Burn Care of the Elderly. J Burn Care Res 38:e625-e628
Abdullahi, Abdikarim; Stanojcic, Mile; Parousis, Alexandra et al. (2017) Modeling Acute ER Stress in Vivo and in Vitro. Shock 47:506-513
Yousuf, Yusef; Jeschke, Marc G; Shah, Ahmed et al. (2017) The response of muscle progenitor cells to cutaneous thermal injury. Stem Cell Res Ther 8:234
Auger, Christopher; Sivayoganathan, Thibacg; Abdullahi, Abdikarim et al. (2017) Hepatic mitochondrial bioenergetics in aged C57BL/6 mice exhibit delayed recovery from severe burn injury. Biochim Biophys Acta 1863:2705-2714
Shih, Jessica G; Shahrokhi, Shahriar; Jeschke, Marc G (2017) Review of Adult Electrical Burn Injury Outcomes Worldwide: An Analysis of Low-Voltage vs High-Voltage Electrical Injury. J Burn Care Res 38:e293-e298
Auger, Christopher; Samadi, Osai; Jeschke, Marc G (2017) The biochemical alterations underlying post-burn hypermetabolism. Biochim Biophys Acta 1863:2633-2644
Mason, Stephanie A; Nathens, Avery B; Byrne, James P et al. (2017) Burn center care reduces acute health care utilization after discharge: A population-based analysis of 1,895 survivors of major burn injury. Surgery 162:891-900
Abdullahi, Abdikarim; Jeschke, Marc G (2017) Taming the Flames: Targeting White Adipose Tissue Browning in Hypermetabolic Conditions. Endocr Rev 38:538-549

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