Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital of Zurich, Zurich, Switzerland.
CNRS, UMR7622, Institut de Biologie Paris-Seine (IBPS), France Sorbonne Universités, UPMC Université Paris 06, UMR7622-IBPS, France INSERM U969, Paris, France.
Br J Pharmacol. 2017 Nov;174(21):3865-3880. doi: 10.1111/bph.13984. Epub 2017 Sep 20.
Pancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease.
We analysed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models. The functional relevance of class I HDACs was tested with the selective inhibitor MS-275 in vivo upon pancreatitis induction and in vitro in activated macrophages and primary acinar cell explants.
HDAC expression and activity were up-regulated in a time-dependent manner following induction of pancreatitis, with the highest abundance observed for class I HDACs. Class I HDAC inhibition did not prevent the initial acinar cell damage. However, it effectively reduced the infiltration of inflammatory cells, including macrophages and T cells, in both acute and chronic phases of the disease, and directly disrupted macrophage activation. In addition, MS-275 treatment reduced DNA damage in acinar cells and limited acinar de-differentiation into acinar-to-ductal metaplasia in a cell-autonomous manner by impeding the EGF receptor signalling axis.
These results demonstrate that class I HDACs are critically involved in the development of acute and chronic forms of pancreatitis and suggest that blockade of class I HDAC isoforms is a promising target to improve the outcome of the disease.
胰腺炎是一种常见的胰腺炎症，在许多国家的发病率都在上升。尽管诊断技术有所提高，但该疾病仍然与严重发病率和死亡率的高风险相关，因此迫切需要新的治疗干预措施。在这项研究中，我们评估了组蛋白去乙酰化酶（HDACs），即基因转录的关键表观遗传调控因子，是否参与了疾病的发生。
我们使用不同的转基因小鼠模型分析了在鹅膏蕈碱诱导的急性、慢性和自身免疫性胰腺炎中 HDAC 的调节。使用选择性抑制剂 MS-275 在体内诱导胰腺炎和体外激活巨噬细胞和原代腺泡细胞外植体时，测试了 I 类 HDAC 的功能相关性。
在诱导胰腺炎后，HDAC 的表达和活性呈时间依赖性上调，其中 I 类 HDAC 的丰度最高。I 类 HDAC 抑制并不能预防初始的腺泡细胞损伤。然而，它在疾病的急性和慢性阶段都能有效地减少炎症细胞（包括巨噬细胞和 T 细胞）的浸润，并直接破坏巨噬细胞的激活。此外，MS-275 治疗以细胞自主的方式减少了腺泡细胞中的 DNA 损伤，并通过阻碍表皮生长因子受体信号通路，限制了腺泡细胞向导管上皮细胞的化生。
这些结果表明，I 类 HDACs 参与了急性和慢性胰腺炎的发生发展，并且抑制 I 类 HDAC 同工型可能是改善该疾病预后的一个有前途的靶点。
