Severe burn-induced endoplasmic reticulum stress and hepatic damage in mice

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

Research output: Contribution to journalArticle

34 Citations (Scopus)

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 1α (IRE-1α) 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.

Original languageEnglish (US)
Pages (from-to)316-320
Number of pages5
JournalMolecular Medicine
Volume15
Issue number9-10
DOIs
StatePublished - Sep 2009

Fingerprint

Endoplasmic Reticulum Stress
Burns
Liver
Hepatocytes
Apoptosis
Wounds and Injuries
Unfolded Protein Response
Liver Diseases
Up-Regulation
Endoplasmic Reticulum
Calnexin
Calreticulin
Protein Disulfide-Isomerases
Calcium
Proteins
Inositol
Heat-Shock Proteins
Serum Albumin
Caspase 3
Protein Kinases

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Severe burn-induced endoplasmic reticulum stress and hepatic damage in mice. / Song, Juquan; Finnerty, Celeste; Herndon, David; Boehning, Darren; Jeschke, Marc G.

In: Molecular Medicine, Vol. 15, No. 9-10, 09.2009, p. 316-320.

Research output: Contribution to journalArticle

Song, Juquan ; Finnerty, Celeste ; Herndon, David ; Boehning, Darren ; Jeschke, Marc G. / Severe burn-induced endoplasmic reticulum stress and hepatic damage in mice. In: Molecular Medicine. 2009 ; Vol. 15, No. 9-10. pp. 316-320.
@article{6862e64b0e2c4496bb9026bc57fa3788,
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 1α (IRE-1α) 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.",
author = "Juquan Song and Celeste Finnerty and David Herndon and Darren Boehning and Jeschke, {Marc G.}",
year = "2009",
month = "9",
doi = "10.2119/molmed.2009.00048",
language = "English (US)",
volume = "15",
pages = "316--320",
journal = "Molecular Medicine",
issn = "1076-1551",
publisher = "Feinstein Institute for Medical Research",
number = "9-10",

}

TY - JOUR

T1 - Severe burn-induced endoplasmic reticulum stress and hepatic damage in mice

AU - Song, Juquan

AU - Finnerty, Celeste

AU - Herndon, David

AU - Boehning, Darren

AU - Jeschke, Marc G.

PY - 2009/9

Y1 - 2009/9

N2 - 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 1α (IRE-1α) 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.

AB - 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 1α (IRE-1α) 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.

UR - http://www.scopus.com/inward/record.url?scp=70149092536&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70149092536&partnerID=8YFLogxK

U2 - 10.2119/molmed.2009.00048

DO - 10.2119/molmed.2009.00048

M3 - Article

VL - 15

SP - 316

EP - 320

JO - Molecular Medicine

JF - Molecular Medicine

SN - 1076-1551

IS - 9-10

ER -