TY - JOUR
T1 - The Role of Macrophage Migration Inhibitory Factor in Remote Ischemic Conditioning Induced Hepatoprotection in a Rodent Model of Liver Transplantation
AU - Emontzpohl, Christoph
AU - Stoppe, Christian
AU - Theissen, Alexander
AU - Beckers, Christian
AU - Neumann, Ulf P.
AU - Lurje, Georg
AU - Ju, Cynthia
AU - Bernhagen, Juergen
AU - Tolba, Rene H.
AU - Czigany, Zoltan
N1 - Funding Information:
This study was supported by the B. Braun Foundation, Melsungen, Germany (B. Braun-Stiftung; BBST-S-17-00240 to ZC; 2017) and by the German Research Foundation (Deutsche Forschungsgemeinschaft; STO 1099/-2 to CS and BE 1977/9-1 to JB; 2015). The authors report no conflicts of interest.
Publisher Copyright:
© 2019 by the Shock Society.
PY - 2019/11
Y1 - 2019/11
N2 - Background: Macrophage migration inhibitory factor (MIF) is an important stress-regulating mediator of acute ischemia/reperfusion (I/R) injury and ischemic conditioning. The present study aimed to investigate whether MIF is involved in the effects of remote ischemic conditioning (RIC) in a rat model of orthotopic liver transplantation (OLT). Methods: OLTs were performed in male Lewis rats (245 g-340 g). Recipients were allocated in a randomized fashion into three experimental groups: remote preconditioning-RIPC, remote post-conditioning-RIPOST, control. RIC was applied as 4x5-5 min I/R via clamping of the infrarenal aorta. Animals were followed for 1, 3, 24, 168 h post-reperfusion (n = 6 recipient/group/time point). Graft micro- and macrocirculation and hepatocellular damage were assessed. Messenger ribonucleic acid (mRNA) expression, serum, and tissue protein levels of MIF, as well as additional markers of I/R injury, were measured. Results: RIC resulted in a prominent downregulation of MIF mRNA, serum, and tissue protein. Compared with control, hepatocellular damage was significantly mitigated after RIPC or RIPOST (serum ALT; RIPC, RIPOST vs. Control, P = 0.008, P = 0.030, respectively). Graft circulation was better preserved in the RIC groups. Furthermore, there was a significant positive correlation between serum MIF and transaminase levels (r = 0.330; P = 0.02). RIC showed a significant effect on iNOS and STAT5 mRNA expressions. Supporting findings were obtained from the measurements of tissue CXCL12 mRNA expression and pAkt/Akt, pErk/Erk. Conclusion: In this sophisticated experimental model of OLT, RIC-induced hepatoprotective effects were associated with a downregulation of MIF at mRNA and protein levels, suggesting the role of MIF as a mediator in RIC-induced protection following OLT.
AB - Background: Macrophage migration inhibitory factor (MIF) is an important stress-regulating mediator of acute ischemia/reperfusion (I/R) injury and ischemic conditioning. The present study aimed to investigate whether MIF is involved in the effects of remote ischemic conditioning (RIC) in a rat model of orthotopic liver transplantation (OLT). Methods: OLTs were performed in male Lewis rats (245 g-340 g). Recipients were allocated in a randomized fashion into three experimental groups: remote preconditioning-RIPC, remote post-conditioning-RIPOST, control. RIC was applied as 4x5-5 min I/R via clamping of the infrarenal aorta. Animals were followed for 1, 3, 24, 168 h post-reperfusion (n = 6 recipient/group/time point). Graft micro- and macrocirculation and hepatocellular damage were assessed. Messenger ribonucleic acid (mRNA) expression, serum, and tissue protein levels of MIF, as well as additional markers of I/R injury, were measured. Results: RIC resulted in a prominent downregulation of MIF mRNA, serum, and tissue protein. Compared with control, hepatocellular damage was significantly mitigated after RIPC or RIPOST (serum ALT; RIPC, RIPOST vs. Control, P = 0.008, P = 0.030, respectively). Graft circulation was better preserved in the RIC groups. Furthermore, there was a significant positive correlation between serum MIF and transaminase levels (r = 0.330; P = 0.02). RIC showed a significant effect on iNOS and STAT5 mRNA expressions. Supporting findings were obtained from the measurements of tissue CXCL12 mRNA expression and pAkt/Akt, pErk/Erk. Conclusion: In this sophisticated experimental model of OLT, RIC-induced hepatoprotective effects were associated with a downregulation of MIF at mRNA and protein levels, suggesting the role of MIF as a mediator in RIC-induced protection following OLT.
KW - Cold storage
KW - ischemia
KW - ischemic conditioning
KW - liver transplantation
KW - macrophage migration inhibitory factor
KW - remote conditioning
KW - reperfusion
KW - REPERFUSION INJURY
KW - RESPONSES
KW - PROTEINS
KW - PROTECTS
KW - RELEASE
U2 - 10.1097/SHK.0000000000001307
DO - 10.1097/SHK.0000000000001307
M3 - Article
C2 - 30601408
SN - 1073-2322
VL - 52
SP - E124-E134
JO - Shock
JF - Shock
IS - 5
ER -