Calcium and ER stress mediate hepatic apoptosis after burn injury

Marc G. Jeschke, Gerd G. Gauglitz, Juquan Song, Gabriela A. Kulp, Celeste Finnerty, Robert A. Cox, José M. Barral, David Herndon, Darren Boehning

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60% total body surface area burn) and sacrificed at various time-points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn-induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function - effects which may be mediated by increased calcium release by inositol 1,4,5-trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury.

Original languageEnglish (US)
Pages (from-to)1857-1865
Number of pages9
JournalJournal of Cellular and Molecular Medicine
Volume13
Issue number8 B
DOIs
StatePublished - Aug 2009

Fingerprint

Endoplasmic Reticulum Stress
Apoptosis
Calcium
Hepatocytes
Liver
Wounds and Injuries
Hot Temperature
Endoplasmic Reticulum
Homeostasis
Purinergic Agonists
Inositol 1,4,5-Trisphosphate Receptors
Body Surface Area
Vasopressins
Transmission Electron Microscopy
Burns
Mass Spectrometry
Adenosine Triphosphate
Western Blotting
Survival

Keywords

  • Apoptosis
  • Calcium
  • ER stress
  • Liver
  • Thermal injury
  • Unfolded protein response

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

Calcium and ER stress mediate hepatic apoptosis after burn injury. / Jeschke, Marc G.; Gauglitz, Gerd G.; Song, Juquan; Kulp, Gabriela A.; Finnerty, Celeste; Cox, Robert A.; Barral, José M.; Herndon, David; Boehning, Darren.

In: Journal of Cellular and Molecular Medicine, Vol. 13, No. 8 B, 08.2009, p. 1857-1865.

Research output: Contribution to journalArticle

Jeschke, MG, Gauglitz, GG, Song, J, Kulp, GA, Finnerty, C, Cox, RA, Barral, JM, Herndon, D & Boehning, D 2009, 'Calcium and ER stress mediate hepatic apoptosis after burn injury', Journal of Cellular and Molecular Medicine, vol. 13, no. 8 B, pp. 1857-1865. https://doi.org/10.1111/j.1582-4934.2009.00644.x
Jeschke, Marc G. ; Gauglitz, Gerd G. ; Song, Juquan ; Kulp, Gabriela A. ; Finnerty, Celeste ; Cox, Robert A. ; Barral, José M. ; Herndon, David ; Boehning, Darren. / Calcium and ER stress mediate hepatic apoptosis after burn injury. In: Journal of Cellular and Molecular Medicine. 2009 ; Vol. 13, No. 8 B. pp. 1857-1865.
@article{9d31b4904d5f4d5184166921aadf69e0,
title = "Calcium and ER stress mediate hepatic apoptosis after burn injury",
abstract = "A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60{\%} total body surface area burn) and sacrificed at various time-points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn-induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function - effects which may be mediated by increased calcium release by inositol 1,4,5-trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury.",
keywords = "Apoptosis, Calcium, ER stress, Liver, Thermal injury, Unfolded protein response",
author = "Jeschke, {Marc G.} and Gauglitz, {Gerd G.} and Juquan Song and Kulp, {Gabriela A.} and Celeste Finnerty and Cox, {Robert A.} and Barral, {Jos{\'e} M.} and David Herndon and Darren Boehning",
year = "2009",
month = "8",
doi = "10.1111/j.1582-4934.2009.00644.x",
language = "English (US)",
volume = "13",
pages = "1857--1865",
journal = "Journal of Cellular and Molecular Medicine",
issn = "1582-1838",
publisher = "Wiley-Blackwell",
number = "8 B",

}

TY - JOUR

T1 - Calcium and ER stress mediate hepatic apoptosis after burn injury

AU - Jeschke, Marc G.

AU - Gauglitz, Gerd G.

AU - Song, Juquan

AU - Kulp, Gabriela A.

AU - Finnerty, Celeste

AU - Cox, Robert A.

AU - Barral, José M.

AU - Herndon, David

AU - Boehning, Darren

PY - 2009/8

Y1 - 2009/8

N2 - A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60% total body surface area burn) and sacrificed at various time-points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn-induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function - effects which may be mediated by increased calcium release by inositol 1,4,5-trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury.

AB - A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60% total body surface area burn) and sacrificed at various time-points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn-induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function - effects which may be mediated by increased calcium release by inositol 1,4,5-trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury.

KW - Apoptosis

KW - Calcium

KW - ER stress

KW - Liver

KW - Thermal injury

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=70149091640&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70149091640&partnerID=8YFLogxK

U2 - 10.1111/j.1582-4934.2009.00644.x

DO - 10.1111/j.1582-4934.2009.00644.x

M3 - Article

VL - 13

SP - 1857

EP - 1865

JO - Journal of Cellular and Molecular Medicine

JF - Journal of Cellular and Molecular Medicine

SN - 1582-1838

IS - 8 B

ER -