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

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, v...

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Autores principales: El-Hamoly, Tarek, Hajnády, Zoltán, Nagy-Pénzes, Máté, Bakondi, Edina, Regdon, Zsolt, Demény, Máté A., Kovács, Katalin, Hegedűs, Csaba, Abd El-Rahman, Sahar S., Szabó, Éva, Maléth, József, Hegyi, Péter, Virág, László
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037143/
https://www.ncbi.nlm.nih.gov/pubmed/33808340
http://dx.doi.org/10.3390/ijms22073593
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author El-Hamoly, Tarek
Hajnády, Zoltán
Nagy-Pénzes, Máté
Bakondi, Edina
Regdon, Zsolt
Demény, Máté A.
Kovács, Katalin
Hegedűs, Csaba
Abd El-Rahman, Sahar S.
Szabó, Éva
Maléth, József
Hegyi, Péter
Virág, László
author_facet El-Hamoly, Tarek
Hajnády, Zoltán
Nagy-Pénzes, Máté
Bakondi, Edina
Regdon, Zsolt
Demény, Máté A.
Kovács, Katalin
Hegedűs, Csaba
Abd El-Rahman, Sahar S.
Szabó, Éva
Maléth, József
Hegyi, Péter
Virág, László
author_sort El-Hamoly, Tarek
collection PubMed
description 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.
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spelling pubmed-80371432021-04-12 Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis El-Hamoly, Tarek Hajnády, Zoltán Nagy-Pénzes, Máté Bakondi, Edina Regdon, Zsolt Demény, Máté A. Kovács, Katalin Hegedűs, Csaba Abd El-Rahman, Sahar S. Szabó, Éva Maléth, József Hegyi, Péter Virág, László Int J Mol Sci Article 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. MDPI 2021-03-30 /pmc/articles/PMC8037143/ /pubmed/33808340 http://dx.doi.org/10.3390/ijms22073593 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
El-Hamoly, Tarek
Hajnády, Zoltán
Nagy-Pénzes, Máté
Bakondi, Edina
Regdon, Zsolt
Demény, Máté A.
Kovács, Katalin
Hegedűs, Csaba
Abd El-Rahman, Sahar S.
Szabó, Éva
Maléth, József
Hegyi, Péter
Virág, László
Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis
title Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis
title_full Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis
title_fullStr Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis
title_full_unstemmed Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis
title_short Poly(ADP-Ribose) Polymerase 1 Promotes Inflammation and Fibrosis in a Mouse Model of Chronic Pancreatitis
title_sort poly(adp-ribose) polymerase 1 promotes inflammation and fibrosis in a mouse model of chronic pancreatitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037143/
https://www.ncbi.nlm.nih.gov/pubmed/33808340
http://dx.doi.org/10.3390/ijms22073593
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