Ako Soichiro, Teper Yaroslav, Ye Linda, Sinnett-Smith James, Hines Oscar J, Rozengurt Enrique, Eibl Guido
Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, California.
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
Gastro Hep Adv. 2022;1(4):640-651. doi: 10.1016/j.gastha.2022.04.012. Epub 2022 Apr 25.
Animal data show that the presence of an oncogenic Kras mutation in pancreatic acinar cells leads to acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC). Inflammatory macrophages play an important role in the formation of ADMs and transition to PanINs. Epidemiologically, statins are associated with a reduced risk of PDAC. We investigated whether statins inhibit inflammatory cytokine production in macrophages and whether this leads to reduced ADM formation.
The efficacy of statins on inflammatory cytokine production in 2 macrophage cell lines was measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of macrophage-conditioned medium on ADM in primary pancreatic acinar cells was investigated. Mouse pancreatic tissue samples were analyzed for macrophage numbers, cytokine levels, and neoplastic/dysplastic area.
Lipophilic statins prevented inflammatory cytokine production in Raw264.7 and J774A.1 cells stimulated by lipopolysaccharide. The inhibitory effect of statins was mediated by inhibition of mevalonate and geranylgeranyl pyrophosphate synthesis and disruption of the actin cytoskeleton but not by a reduction in intracellular cholesterol. Treatment of macrophages with lipophilic statins also blocked ADM formation of primary pancreatic acinar cells. Furthermore, oral administration of simvastatin was associated with a reduction in the number of intrapancreatic macrophages, decreased inflammatory cytokine levels in the pancreas, and attenuated ADM/PanIN formation in mice.
Our data support the hypothesis that statins oppose early PDAC development by their effects on macrophages and ADM formation. The inhibitory actions of statins on macrophages may collaborate with direct inhibitory effects on transformed pancreatic epithelial cells, which cumulatively may reduce early PDAC development and progression.
动物数据表明，胰腺腺泡细胞中致癌性Kras突变的存在会导致腺泡-导管化生（ADM）、胰腺上皮内瘤变（PanIN）和胰腺导管腺癌（PDAC）。炎性巨噬细胞在ADM的形成以及向PanIN的转变中起重要作用。从流行病学角度看，他汀类药物与PDAC风险降低相关。我们研究了他汀类药物是否抑制巨噬细胞中炎性细胞因子的产生，以及这是否会导致ADM形成减少。
通过实时聚合酶链反应和酶联免疫吸附测定法检测他汀类药物对2种巨噬细胞系中炎性细胞因子产生的疗效。研究了巨噬细胞条件培养基对原代胰腺腺泡细胞中ADM的影响。对小鼠胰腺组织样本进行分析，检测巨噬细胞数量、细胞因子水平以及肿瘤/发育异常区域。
亲脂性他汀类药物可阻止脂多糖刺激的Raw264.7和J774A.1细胞产生炎性细胞因子。他汀类药物的抑制作用是通过抑制甲羟戊酸和香叶基香叶基焦磷酸的合成以及破坏肌动蛋白细胞骨架介导的，而不是通过降低细胞内胆固醇。用亲脂性他汀类药物处理巨噬细胞也可阻断原代胰腺腺泡细胞的ADM形成。此外，口服辛伐他汀与胰腺内巨噬细胞数量减少、胰腺中炎性细胞因子水平降低以及小鼠ADM/PanIN形成减弱有关。
我们的数据支持以下假设，即他汀类药物通过对巨噬细胞和ADM形成的作用来对抗早期PDAC的发展。他汀类药物对巨噬细胞的抑制作用可能与对转化的胰腺上皮细胞的直接抑制作用协同发挥作用，这可能会累积降低早期PDAC的发展和进展。
