title: Neuropeptide PACAP in mouse liver ischemia and reperfusion injury: immunomodulation by the cAMP-PKA pathway.
abstract: Hepatic ischemia and reperfusion injury (IRI), an exogenous antigen-independent local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The immune system and the nervous system maintain extensive communication and mount a variety of integrated responses to danger signals through intricate chemical messengers. This study examined the function and potential therapeutic potential of neuropeptide pituitary adenylate cyclase-activating polypeptides (PACAP) in a murine model of partial liver "warm" ischemia (90 minutes) followed by reperfusion. Liver IRI readily triggered the expression of intrinsic PACAP and its receptors, whereas the hepatocellular damage was exacerbated in PACAP-deficient mice. Conversely, PACAP27, or PACAP38 peptide monotherapy, which elevates intracellular cyclic adenosine monophosphate/protein kinase A (cAMP-PKA) signaling, protected livers from IRI, as evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. The liver protection rendered by PACAP peptides was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and selectively augmented hepatic interleukin (IL)-10 expression. Strikingly, PKA inhibition readily restored liver damage in otherwise IR-resistant, PACAP-conditioned mice. In vitro, PACAP treatment not only diminished macrophage tumor necrosis factor alpha/IL-6/IL-12 levels in a PKA-dependent manner, but also prevented necrosis and apoptosis in primary mouse hepatocyte cultures.
  
  
  CONCLUSIONS
  Our novel findings document the importance of PACAP-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 manage liver inflammation and 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 90095, USA.
authors.forename: Haofeng
authors.initials: H
authors.lastname: Ji
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiu-da
authors.initials: XD
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Cynthia Y
authors.initials: CY
authors.lastname: Huang
authors.forename: Catalina
authors.initials: C
authors.lastname: Abad
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 / Q000276:immunology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000276:immunology; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism*; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000276:immunology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: C495402:Adcyap1 protein, mouse; D007155:Immunologic Factors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases