Insulin protects against hepatic damage postburn.
Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.
Shriners Hospitals for Children, The University of Texas Medical Branch, Galveston, Texas, USA. marc.jeschke@sunnybrook.ca
Marc G
MG
Jeschke
Robert
R
Kraft
Juquan
J
Song
Gerd G
GG
Gauglitz
Robert A
RA
Cox
Natasha C
NC
Brooks
Celeste C
CC
Finnerty
Gabriela A
GA
Kulp
David N
DN
Herndon
Darren
D
Boehning
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002056:Burns / Q000188:drug therapy*; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin
J Burns Wounds. 2007 Jun 12;7:e1
17625613
Cell Cycle. 2004 Mar;3(3):252-4
14726673
J Biol Chem. 2000 Mar 24;275(12):9047-54
10722755
Diabetologia. 1997 Jul;40 Suppl 2:S2-17
9248696
Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1466-71
15665074
Diabetes Care. 2001 Mar;24(3):588-97
11289486
Science. 2004 Oct 15;306(5695):457-61
15486293
Cell. 2000 May 26;101(5):451-4
10850487
Science. 2006 Aug 25;313(5790):1137-40
16931765
J Hepatol. 2005 Jun;42(6):870-9
15885358
Nat Cell Biol. 2003 Dec;5(12):1051-61
14608362
Arch Surg. 2004 Jun;139(6):641-7
15197091
N Engl J Med. 2001 Nov 8;345(19):1359-67
11794168
Ann Surg. 2004 Aug;240(2):340-9
15273560
Recent Prog Horm Res. 1993;48:291-339
7680139
Am J Respir Crit Care Med. 2010 Aug 1;182(3):351-9
20395554
Surgery. 2008 Oct;144(4):629-35; discussion 635-7
18847648
N Engl J Med. 2006 Feb 2;354(5):449-61
16452557
Mol Med. 2002 Aug;8(8):443-50
12435855
Shock. 2010 Mar;33(3):299-305
22011639
J Cell Biol. 2006 Dec 4;175(5):709-14
17130290
Mol Med. 2009 Sep-Oct;15(9-10):316-20
19603103
Crit Care Med. 2010 Jan;38(1):202-8
19770742
Crit Care Med. 2007 Sep;35(9 Suppl):S519-23
17713402
J Burn Care Rehabil. 1996 Mar-Apr;17(2):95-107
8675512
Ann Surg. 2004 Apr;239(4):553-60
15024317
Mol Med. 2009 Sep-Oct;15(9-10):337-51
19603107
J Surg Res. 1978 Nov;25(5):394-403
713539
Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
17565364
Ann Surg. 2008 Sep;248(3):387-401
18791359
J Burn Care Res. 2008 Sep-Oct;29(5):683-94
18695610
Curr Biol. 2000 Jul 13;10(14):R518-21
10898996
Shock. 2007 Aug;28(2):172-7
17529902
Am J Physiol Gastrointest Liver Physiol. 2001 Jun;280(6):G1314-20
11352826
J Pathol. 1997 Mar;181(3):257-66
9155709
J Cell Mol Med. 2009 Aug;13(8B):1857-65
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