Persistent Hypermetabolism after Severe Burn Injury: Effects of Hepatic Stress and Regeneration

Burn injury represents one of the most severe forms of trauma. Persistent hypermetabolism and inflammatory response are common in major burned patients, contributing to morbidity and mortality. The underlying mechanisms are largely unknown and therefore novel and effective treatments are lacking. Liver is the fundamental mediator of post-burn immunologic and metabolic derangement and significant hepatomegaly is universally present and associated with the persistent hypermetabolism and inflammatory response in severely burned patients. We sought to understand if such a hepatomegaly is the consequence of 1) increased hepatic fat infiltration due to intensified lipolysis in white adipose tissue (WAT) and inter-organ cross-talk between liver and WAT, or 2)aberrant liver regeneration induced by stress response and liver damage which carries on hypermetabolic and pro-inflammatory signaling, contributing to persistent hypermetabolism and inflammatory response after major burn injury. Rodent models of burn plus LPS administration, high fat diet (HFD) plus burn, and 30% TBSA burn of Sox9-cre/ERT2:ROSA26-EYFP mice were used for the studies. In the rat model of burn plus LPS, we demonstrated 1) increased ER stress, inflammasome activation, apoptosis and lipolysis in WAT,contributing to liver steatosis (Chapter 2);2) hepatic ER stress and inflammasome activation, contributing to liver damage and organ dysfunction(Chapter 3). In the mouse model of HFD plus burn, we showed that hepatic fat infiltration and meta-flammation augment the liver damage and metabolic dysfunction post-burn(Chapter 4). We lineage-traced the facultative liver progenitor cells after burn injury and demonstrated that liver regeneration by this group of cells peaked around 2 weeks post-burn. Significant activation of multiple inflammatory and metabolic signaling pathways was indicated by transcriptomic analysis and verified by further analysis in the liver stem cells and their progeny post-burn as compared with both sham and self-renewal mature hepatocytes. Concomitant down-regulation of LXR signaling in the liver stem cells post-burn implicated the therapeutic potential of LXR agonist in ameliorating pro-inflammatory response and restoring lipid homeostasis after major burn injury (Chapter 5). In conclusion, severe burn injury leads to hepatic stress response, liver damage and steatosis, stimulating liver regeneration from facultative stem cells which contributes to persistent hypermetabolism and pro-inflammatory response.Ph.D