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.
Highlights
Pancreatitis, an inflammatory disease of the pancreas, affects both the exocrine and endocrine functions of the organ [1]
Chronic pancreatitis is an inflammatory disease of the pancreas affecting mainly the exocrine function of the organ
Repeated episodes of acute inflammation accompanied by acinar cell necrosis and impaired ductal secretion leads to progressive damage of the exocrine pancreas [2,23]
Summary
Pancreatitis, an inflammatory disease of the pancreas, affects both the exocrine and endocrine functions of the organ [1]. Advances in the analysis of the genetic background of CP identified mutations and single nucleotide polymorphisms (SNPs) in trypsinogen, protease inhibitors and ion channels. Based on these discoveries, in the last two decades two complementary theories emerged to explain the pathomechanism of CP. In the last two decades two complementary theories emerged to explain the pathomechanism of CP One of these focuses on abnormalities of trypsinogen activation as exemplified by gain of function mutations in cationic trypsinogen (PRSS1) [5] or loss of function mutations in the serine protease inhibitor kazaltype 1 (SPINK1) [6]. CP-associated mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel are in line with this latter theory
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