title: Vasoactive intestinal peptide attenuates liver ischemia/reperfusion injury in mice via the cyclic adenosine monophosphate-protein kinase a pathway.
abstract: Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liver ischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self-healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP-treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor α/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients.
authors.affiliation: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors.forename: Haofeng
authors.initials: H
authors.lastname: Ji
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuanxing
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiu-Da
authors.initials: XD
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Terry T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: James A
authors.initials: JA
authors.lastname: Waschek
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005434:Flow Cytometry / Q000379:methods; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D007107:Immune System; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009504:Neutrophils / Q000166:cytology; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology*; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000737:chemistry*
chemical_list: D016753:Interleukin-10; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3