Inflammatory disorders of the pancreas are divided into acute (AP) and chronic (CP) forms. Both states of pancreatitis are a result of pro-inflammatory mediators, including reactive oxygen species (ROS). One of the sources of ROS is NADPH oxidase (Nox). The rodent genome encodes Nox1-4, Duox1 and Duox2. Our purpose was to assess the extent to which Nox enzymes contribute to the pathogenesis of both AP and CP using Nox-deficient mice. Using RT-PCR, Nox1 was found in both isolated mouse pancreatic acini and pancreatic stellate cells (PaSCs). Subsequently, mice with genetically deleted Nox1 were further studied and showed that the histo-morphologic characteristics of caerulein-induced CP, but not caerulein-induced AP, was ameliorated in Nox1 KO mice. We also found that the lack of Nox1 impaired caerulein-induced ROS generation in PaSCs. Using Western blotting, we found that AKT mediates the fibrotic effect of Nox1 in a mouse model of CP. We also found a decrease in phospho-ERK and p38MAPK levels in Nox1 KO mice with CP, but not with AP. Both CP-induced TGF-β up-regulation and NF-ĸB activation were impaired in pancreas from Nox1 KO mice. Western blotting indicated increases in proteins involved in fibrosis and acinar-to-ductal metaplasia in WT mice with CP. No change in those proteins were observed in Nox1 KO mice. The lack of Nox1 lowered mRNA levels of CP-induced matrix metalloproteinase MMP-9 and E-cadherin repressor Twist in PaSCs. CONCLUSION: Nox1-derived ROS in PaSCs mediate the fibrotic process of CP by activating the downstream redox-sensitive signaling pathways AKT and NF-ĸB, up-regulating MMP-9 and Twist, and producing α-smooth muscle actin and collagen I and III.

中文翻译：

---

NADPH 氧化酶 1 介导慢性胰腺炎中雨蛙素诱导的胰腺纤维化。

胰腺炎症性疾病分为急性（AP）和慢性（CP）形式。胰腺炎的两种状态都是促炎介质（包括活性氧（ROS））的结果。ROS 的来源之一是 NADPH 氧化酶 (Nox)。啮齿动物基因组编码 Nox1-4、Duox1 和 Duox2。我们的目的是使用 Nox 缺陷小鼠评估 Nox 酶对 AP 和 CP 发病机制的影响程度。使用 RT-PCR，在分离的小鼠胰腺腺泡和胰腺星状细胞 (PaSC) 中发现了 Nox1。随后，对 Nox1 基因缺失的小鼠进行了进一步研究，结果表明，在 Nox1 KO 小鼠中，雨蛙素诱导的 CP（而非雨蛙素诱导的 AP）的组织形态学特征得到改善。我们还发现，Nox1 的缺乏会损害 PaSC 中雨蛙素诱导的 ROS 生成。使用蛋白质印迹法，我们发现 AKT 在 CP 小鼠模型中介导 Nox1 的纤维化作用。我们还发现，CP 组的 Nox1 KO 小鼠磷酸化 ERK 和 p38MAPK 水平下降，而 AP 组则没有。Nox1 KO 小鼠胰腺中 CP 诱导的 TGF-β 上调和 NF-κB 激活均受损。蛋白质印迹表明，患有 CP 的 WT 小鼠中参与纤维化和腺泡导管化生的蛋白质增加。在 Nox1 KO 小鼠中没有观察到这些蛋白质的变化。Nox1 的缺乏降低了 PaSC 中 CP 诱导的基质金属蛋白酶 MMP-9 和 E-钙粘蛋白阻遏蛋白 Twist 的 mRNA 水平。结论: PaSCs 中 Nox1 衍生的 ROS 通过激活下游氧化还原敏感信号通路 AKT 和 NF-ĸB、上调 MMP-9 和 Twist、产生 α-平滑肌肌动蛋白以及 I 型和 III 型胶原蛋白介导 CP 纤维化过程。