Severe Burn-Induced Endoplasmic Reticulum Stress and Hepatic Damage in Mice

Juquan Song,David N Herndon,Darren Boehning,Celeste C Finnerty,Marc G Jeschke

doi:10.2119/molmed.2009.00048

Abstract

Severe burn injury results in liver dysfunction and damage, with subsequent metabolic derangements contributing to patient morbidity and mortality. On a cellular level, significant postburn hepatocyte apoptosis occurs and likely contributes to liver dysfunction. However, the underlying mechanisms of hepatocyte apoptosis are poorly understood. The endoplasmic reticulum (ER) stress response/unfolded protein response (UPR) pathway can lead to hepatocyte apoptosis under conditions of liver dysfunction. Thus, we hypothesized that ER stress/UPR may mediate hepatic dysfunction in response to burn injury. We investigated the temporal activation of hepatic ER stress in mice after a severe burn injury. Mice received a scald burn over 35% of their body surface and were killed at 1, 7, 14, and 21 d postburn. We found that severe burn induces hepatocyte apoptosis as indicated by increased caspase-3 activity (P < 0.05). Serum albumin levels decreased postburn and remained lowered for up to 21 d, indicating that constitutive secretory protein synthesis was reduced. Significantly, upregulation of the ER stress markers glucose-related protein 78 (GRP78)/BIP, protein disulfide isomerase (PDI), p-protein kinase R-like endoplasmic reticulum kinase (p-PERK), and inositol-requiring enzyme 1alpha (IRE-1alpha) were found beginning 1 d postburn (P < 0.05) and persisted up to 21 d postburn (P < 0.05). Hepatic ER stress induced by burn injury was associated with compensatory upregulation of the calcium chaperone/storage proteins calnexin and calreticulin (P < 0.05), suggesting that ER calcium store depletion was the primary trigger for induction of the ER stress response. In summary, thermal injury in mice causes long-term adaptive and deleterious hepatic function alterations characterized by significant upregulation of the ER stress response.

Highlights

Severe burn injury causes myriad metabolic alterations, including hyperglycemia, lipolysis, and protein catabolism [1]
The expression of endoplasmic reticulum (ER) luminal chaperones calnexin and calreticulin were significantly increased at 1 d postburn in mice, and remained elevated 21 d later (P < 0.05) (Figure 4C, D), suggesting that ER stress was activated by depletion of intracellular calcium stores
These findings indicate that burn injury in mice caused long-term activation of the ER stress response, hepatocyte apoptosis, and hepatic dysfunction lasting for 21 d

Summary

Introduction

Severe burn injury causes myriad metabolic alterations, including hyperglycemia, lipolysis, and protein catabolism [1]. These changes can induce multiorgan failure and sepsis leading to significant morbidity and mortality [2,3]. By modulating metabolic and immune responses, the liver plays a pivotal role in mediating survival and recovery of burn patients [4,5,6]. Preexisting liver disease is directly associated with adverse clinical outcomes following burn injury. Ways to improve recovery and survival of patients with severe burns may be developed through better understanding of the mechanisms that mediate the pathophysiologic changes in the liver following thermal injury

Methods

Results

Conclusion