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.
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.
|Yan, Jinhui; Hill, William F; Rehou, Sarah et al. (2018) Sepsis criteria versus clinical diagnosis of sepsis in burn patients: A validation of current sepsis scores. Surgery 164:1241-1245|
|Dolp, Reinhard; Rehou, Sarah; McCann, Matthew R et al. (2018) Contributors to the length-of-stay trajectory in burn-injured patients. Burns 44:2011-2017|
|Amini-Nik, Saeid; Yousuf, Yusef; Jeschke, Marc G (2018) Scar management in burn injuries using drug delivery and molecular signaling: Current treatments and future directions. Adv Drug Deliv Rev 123:135-154|
|Stanojcic, Mile; Abdullahi, Abdikarim; Rehou, Sarah et al. (2018) Pathophysiological Response to Burn Injury in Adults. Ann Surg 267:576-584|
|Bakhtyar, Nazihah; Jeschke, Marc G; Herer, Elaine et al. (2018) Exosomes from acellular Wharton's jelly of the human umbilical cord promotes skin wound healing. Stem Cell Res Ther 9:193|
|Jeschke, Marc G; Shahrokhi, Shahriar; Finnerty, Celeste C et al. (2018) Wound Coverage Technologies in Burn Care: Established Techniques. J Burn Care Res 39:313-318|
|Auger, Christopher; Sivayoganathan, Thibacg; Abdullahi, Abdikarim et al. (2018) Metformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction. Sci Rep 8:5646|
|Hakimi, Navid; Cheng, Richard; Leng, Lian et al. (2018) Handheld skin printer: in situ formation of planar biomaterials and tissues. Lab Chip 18:1440-1451|
|Sadiq, Alia; Shah, Ahmed; Jeschke, Marc G et al. (2018) The Role of Serotonin during Skin Healing in Post-Thermal Injury. Int J Mol Sci 19:|
|McCann, Matthew R; Hill, William F; Yan, Jinhui et al. (2018) Burn injury and multiple sclerosis: A retrospective case-control study. Burns :|
Showing the most recent 10 out of 99 publications