Neuropeptide PACAP in mouse liver ischemia and reperfusion injury: Immunomodulation by the cAMP-PKA pathway

Authors

  • Haofeng Ji,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Yu Zhang,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
    2. Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Xiu-da Shen,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Feng Gao,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Cynthia Y. Huang,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Catalina Abad,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Ronald W. Busuttil,

    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • James A. Waschek,

    1. Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Jerzy W. Kupiec-Weglinski

    Corresponding author
    1. Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
    • M.D., Ph.D., Dumont-UCLA Transplant Center, 77-120 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095
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    • fax: 310-267-2358


  • Potential conflict of interest: Nothing to report.

  • See Editorial on Page 878

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. Conclusion: 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. (HEPATOLOGY 2013)

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