title: Severe burn-induced endoplasmic reticulum stress and hepatic damage in mice.
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.
authors: Shriners Hospitals for Children and Departments Surgery, University of Texas Medical Branch, Galveston, Texas, USA.
authors: Juquan
authors: J
authors: Song
authors: Celeste C
authors: CC
authors: Finnerty
authors: David N
authors: DN
authors: Herndon
authors: Darren
authors: D
authors: Boehning
authors: Marc G
authors: MG
authors: Jeschke
mesh_terms: D000818:Animals; D002056:Burns / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D013312:Stress, Physiological; D013997:Time Factors
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; C505409:Casp3 protein, mouse; D053148:Caspase 3