Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice

Abstract

Background/Aims Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. Methods Livers explanted from wild-type, iNOS−/−, JNK1−/− or JNK2−/− mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. Results After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS-deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS-deficiency. JNK inhibition and JNK2-deficiency, but not JNK1-deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS-deficiency, JNK inhibition and JNK2-deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. Conclusion The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization and is an attractive target to improve liver function and survival in CDD liver transplantation.

Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury

“…In this work, liposIA-treated mice had a low mitochondrial ROS and a normal mitochondrial membrane potential. Besides, a growing number of evidence demonstrates that upregulation of iNOS and p-JNK play a key role in mitochondrial dysfunction and cell death 45 - 47 . Here, our results indicated a decrease of iNOS and p-JNK in liposIA-treated mice.…”

Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase3 pathway regulation

“…However, animal studies have primarily focused on graft preservation, including ex vivo machine perfusion and modified perfusates in rat or swine models [46–50]. To our knowledge, only Liu et al have reported syngeneic liver transplants from DCD mice; however, the surgery in their study was performed without hepatic artery reconstruction, which differs from clinical transplant procedures [51]. To strictly adhere to clinical surgery procedures, we first attempted liver transplantation from C57Bl/6 to C57Bl/6 mice; however, because of hepatic artery variations, the transplant surgery success rate was only approximately 30 %, which was not suitable for establishing an animal model.…”

New insights into the role and mechanism of c‐Jun‐N‐terminal kinase signaling in the pathobiology of liver diseases

“…Sab is an outer membrane scaffold protein with one hydrophobic transmembrane domain which separates the N‐terminal SRC homology 3 domain (SH3) domain facing the intermembrane space and the C‐terminal JNK kinase interacting motifs (KIM) facing the cytoplasm . The interaction of P‐JNK and Sab was first recognized in 2002 by Wiltshire et al, and subsequently confirmed by others . In parallel with studies in the liver, interaction of JNK and Sab was observed in Hela cells and inhibited by transactivator of transcription of human immunodeficiency virus (Tat)‐Sab inhibitory peptide (KIM1 20 amino acid peptide linked to membrane permeant Tat peptide).…”