1. Academic Validation
  2. Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis

Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis

  • Int J Mol Sci. 2021 Mar 30;22(7):3593. doi: 10.3390/ijms22073593.
Tarek El-Hamoly 1 2 Zoltán Hajnády 1 3 Máté Nagy-Pénzes 1 3 Edina Bakondi 1 Zsolt Regdon 1 3 Máté A Demény 4 Katalin Kovács 1 4 Csaba Hegedűs 1 Sahar S Abd El-Rahman 5 Éva Szabó 6 József Maléth 7 8 9 Péter Hegyi 10 11 László Virág 1 4
Affiliations

Affiliations

  • 1 Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
  • 2 Drug Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, 11787 Cairo, Egypt.
  • 3 Doctoral School of Molecular Medicine, University of Debrecen, 4032 Debrecen, Hungary.
  • 4 MTA-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary.
  • 5 Department of Pathology, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt.
  • 6 Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
  • 7 First Department of Medicine, University of Szeged, 6720 Szeged, Hungary.
  • 8 HAS-USZ Momentum Epithel Cell Signalling and Secretion Research Group, 6720 Szeged, Hungary.
  • 9 Department of Public Health, University of Szeged, 6720 Szeged, Hungary.
  • 10 János Szentágothai Research Centre, Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary.
  • 11 Momentum Gastroenterology Multidisciplinary Research Group, Hungarian Academy of Sciences, University of Szeged, 6720 Szeged, Hungary.
Abstract

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by ductal obstructions, tissue fibrosis, atrophy and exocrine and endocrine pancreatic insufficiency. However, our understanding is very limited concerning the disease's progression from a single acute inflammation, via recurrent acute pancreatitis (AP) and early CP, to the late stage CP. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor Enzyme activated mostly by oxidative DNA damage. As a co-activator of inflammatory transcription factors, PARP1 is a central mediator of the inflammatory response and it has also been implicated in acute pancreatitis. Here, we set out to investigate whether PARP1 contributed to the pathogenesis of CP. We found that the clinically used PARP Inhibitor olaparib (OLA) had protective effects in a murine model of CP induced by multiple cerulein injections. OLA reduced pancreas atrophy and expression of the inflammatory mediators TNFα and interleukin-6 (IL-6), both in the pancreas and in the lungs. Moreover, there was significantly less fibrosis (Masson's trichrome staining) in the pancreatic sections of OLA-treated mice compared to the cerulein-only group. mRNA expression of the fibrosis markers TGFβ, smooth muscle actin (SMA), and collagen-1 were markedly reduced by OLA. CP was also induced in PARP1 knockout (KO) mice and their wild-type (WT) counterparts. Inflammation and fibrosis markers showed lower expression in the KO compared to the WT mice. Moreover, reduced granulocyte infiltration (tissue myeloperoxidase activity) and a lower elevation of serum amylase and Lipase activity could also be detected in the KO mice. Furthermore, primary acinar cells isolated from KO mice were also protected from cerulein-induced toxicity compared to WT cells. In summary, our data suggest that PARP inhibitors may be promising candidates for repurposing to treat not only acute but chronic pancreatitis as well.

Keywords

cell death; chronic pancreatitis; fibrosis; inflammation; poly(ADP-ribose) polymerase 1.

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