Human heat shock protein 27 overexpressing mice are protected against hepatic ischemia and reperfusion injury.
BACKGROUND
Hepatic ischemia reperfusion injury (IRI) is a major clinical problem during the perioperative period and occurs frequently after major hepatic resection or liver transplantation. Our laboratory previously demonstrated that exogenous A1 adenosine receptor activation protects against renal IRI by upregulation and phosphorylation of heat shock protein 27 (HSP27).


METHODS
This study used mice overexpressing human HSP27 (huHSP27 OE) to determine whether these mice are protected against liver IRI.


RESULTS
After hepatic IR, the huHSP27 OE mice had significant protection against liver injury (reduced alanine transferase) and necrosis (hematoxylin-eosin staining) compared with the HSP27 WT mice. The huHSP27 OE mice also showed less induction of proinflammatory messenger RNA MIP-2, reduced neutrophil infiltration, and decreased apoptosis (caspase 3 fragmentation and DNA laddering) compared with the HSP27 WT mice. Finally, the huHSP27 OE mice showed significantly less disruption of filamentous actin in hepatocytes and bile canaliculi of the ischemic lobes compared with the HSP27 WT mice. Depletion of Kupffer cells with gadolinium chloride provided significant protection against liver IRI in HSP27 WT mice but not in huHSP27 OE mice suggesting that the overexpression of huHSP27 in the Kupffer cells may be responsible for the hepatic protection observed in huHSP27 OE mice.


CONCLUSIONS
Our results show that the overexpression of huHSP27 in Kupffer cells of the liver may be responsible for the protection against hepatic IRI in vivo by reducing necrosis and apoptosis and by stabilizing F-actin with subsequent reductions in inflammation and proinflammatory neutrophil infiltration. Harnessing the mechanisms of cytoprotection with HSP27 may lead to new therapies for the management of perioperative hepatic IRI.
Chen
Sean W C
SW
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA.
Park
Sang Won
SW
Kim
Mihwa
M
Brown
Kevin M
KM
D'Agati
Vivette D
VD
Lee
H Thomas
HT
D000818:Animals; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000517:prevention & control*; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D055551:HSP27 Heat-Shock Proteins; D012333:RNA, Messenger