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Experimental acute pancreatitis in PAP/HIP knock-out mice
  1. Meritxell Gironella1,
  2. Emma Folch-Puy2,
  3. Aude LeGoffic1,
  4. Stéphane Garcia1,
  5. Laurence Christa3,
  6. Andrew Smith4,
  7. Luis Tebar4,
  8. Stephen P Hunt4,
  9. Rosemary Bayne5,
  10. Andrew J H Smith5,
  11. Jean-Charles Dagorn1,
  12. Daniel Closa2,
  13. Juan L Iovanna1
  1. 1INSERM, U.624, F-13009 Marseille, France
  2. 2Department of Experimental Pathology, IIBB-CSIC, IDIBAPS, CIBEREHD Barcelona, Spain
  3. 3Laboratoire de Biochimie Métabolique, Hôpital Necker Enfants-Malades, Paris, France
  4. 4Department of Anatomy and Developmental Biology, University College London, London, UK
  5. 5Gene Targeting Laboratory, Institute for Stem Cell Research, University of Edinburgh, The King’s Buildings, Edinburgh, UK
  1. Correspondence to:
    Dr J L Iovanna
    Centre de Recherche INSERM, Unité 624, Stress Cellulaire, 163 Avenue de Luminy, BP915, 13288 Marseille, France; iovanna{at}marseille.inserm.fr

Abstract

Background and aims: PAP/HIP was first reported as an additional pancreatic secretory protein expressed during the acute phase of pancreatitis. It was shown in vitro to be anti-apoptotic and anti-inflammatory. This study aims to look at whether PAP/HIP plays the same role in vivo.

Methods: A model of caerulein-induced pancreatitis was used to compare the outcome of pancreatitis in PAP/HIP−/− and wild-type mice.

Results: PAP/HIP−/− mice showed the normal phenotype at birth and normal postnatal development. Caerulein-induced pancreatic necrosis was, however, less severe in PAP/HIP−/− mice than in wild-type mice, as judged by lower amylasemia and lipasemia levels and smaller areas of necrosis. On the contrary, pancreas from PAP/HIP−/− mice was more sensitive to apoptosis, in agreement with the anti-apoptotic effect of PAP/HIP in vitro. Surprisingly, pancreatic inflammation was more extensive in PAP/HIP−/− mice, as judged from histological parameters, increased myeloperoxidase activity and increased pro-inflammatory cytokine expression. This result, in apparent contradiction with the limited necrosis observed in these mice, is, however, in agreement with the anti-inflammatory function previously reported in vitro for PAP/HIP. This is supported by the observation that activation of the STAT3/SOCS3 pathway was strongly decreased in the pancreas of PAP/HIP−/− mice and by the reversion of the apoptotic and inflammatory phenotypes upon administration of recombinant PAP/HIP to PAP/HIP−/− mice.

Conclusion: The anti-apoptotic and anti-inflammatory functions described in vitro for PAP/HIP have physiological relevance in the pancreas in vivo during caerulein-induced pancreatitis.

  • IL, interleukin
  • PAP
  • pancreatitis-associated protein
  • PARP, poly(adenosine diphosphate-ribose) polymerase
  • PMN, polymorphonuclear
  • RT–PCR, reverse transcriptase–polymerase chain reaction
  • TBS, Tris-buffered saline
  • TNFα, tumour necrosis factor α

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Footnotes

  • Published Online First 4 April 2007

  • Conflict of interest: None declared.

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