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
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Drug Radiation Research Department, National Centre for Radiation Research and Technology, Atomic Energy Authority, 11787 Cairo, Egypt.
Int J Mol Sci. 2021 Mar 30;22(7):3593. doi: 10.3390/ijms22073593.
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.
慢性胰腺炎（CP）是一种胰腺炎症性疾病，其特征为导管阻塞、组织纤维化、萎缩以及胰腺外分泌和内分泌功能不全。然而，我们对于该疾病从单次急性炎症，经复发性急性胰腺炎（AP）和早期CP发展至晚期CP的过程了解非常有限。聚（ADP-核糖）聚合酶1（PARP1）是一种主要由氧化性DNA损伤激活的DNA损伤传感酶。作为炎症转录因子的共激活因子，PARP1是炎症反应的核心介质，并且也与急性胰腺炎有关。在此，我们着手研究PARP1是否参与CP的发病机制。我们发现，临床使用的PARP抑制剂奥拉帕利（OLA）在多次注射雨蛙肽诱导的CP小鼠模型中具有保护作用。OLA减轻了胰腺萎缩以及胰腺和肺中炎症介质肿瘤坏死因子α（TNFα）和白细胞介素-6（IL-6）的表达。此外，与仅注射雨蛙肽的组相比，OLA处理的小鼠胰腺切片中的纤维化（Masson三色染色）明显减少。OLA显著降低了纤维化标志物转化生长因子β（TGFβ）、平滑肌肌动蛋白（SMA）和胶原蛋白-1的mRNA表达。我们还在PARP1基因敲除（KO）小鼠及其野生型（WT）对照中诱导了CP。与WT小鼠相比，KO小鼠中的炎症和纤维化标志物表达较低。此外，在KO小鼠中还可检测到粒细胞浸润减少（组织髓过氧化物酶活性）以及血清淀粉酶和脂肪酶活性升高幅度较低。此外，与WT细胞相比，从KO小鼠分离的原代腺泡细胞也受到保护，免受雨蛙肽诱导的毒性作用。总之，我们的数据表明，PARP抑制剂可能是有前景的重新利用候选药物，不仅可用于治疗急性胰腺炎，还可用于治疗慢性胰腺炎。
