Experimental acute pancreatitis in PAP/HIP knock-out mice.
OBJECTIVE
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.


CONCLUSIONS
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.
Gironella
Meritxell
M
INSERM, U.624, Marseille, France.
Folch-Puy
Emma
E
LeGoffic
Aude
A
Garcia
Stéphane
S
Christa
Laurence
L
Smith
Andrew
A
Tebar
Luis
L
Hunt
Stephen P
SP
Bayne
Rosemary
R
Smith
Andrew J H
AJ
Dagorn
Jean-Charles
JC
Closa
Daniel
D
Iovanna
Juan L
JL
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000032:analysis; D002108:Ceruletide; D004195:Disease Models, Animal; D051847:Lithostathine / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000473:pathology*; D000073718:Pancreatitis-Associated Proteins; D010641:Phenotype; D011506:Proteins / Q000032:analysis*; D050796:STAT3 Transcription Factor / Q000032:analysis; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis
D001324:Autoantigens; D051847:Lithostathine; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C497615:Reg1 protein, mouse; C490253:Reg3b protein, mouse; C518252:RegII protein, mouse; C088549:RegIII protein, mouse; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D002108:Ceruletide