Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA.
Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA.
Life Sci. 2021 Aug 1;278:119640. doi: 10.1016/j.lfs.2021.119640. Epub 2021 May 25.
Patients with chronic pancreatitis have an increased risk of pancreatic malignancy, but the mechanisms underlying this relationship are poorly understood. We developed a mouse model of chronic pancreatitis by treatment with a combination of cerulein and azoxymethane. In our model, we show that cerulein and azoxymethane treated mice develop pathological malignant phenotype and associated lung inflammation. We observed chronic pancreatitis-associated induction of proinflammatory cytokines such as interleukin-6, interleukin-15, and granulocyte-macrophage colony-stimulating factor, along with accumulation of macrophages and eosinophilic inflammation. We also observed eosinophils degranulation, pancreatic stellate cell activation-mediated epithelial-to-mesenchymal transition-associated proteins that display a pancreatic malignant phenotype including acinar-to-ductal metaplasia and acinar cell atrophy. We observed highly induced interleukin-15 that has been earlier reported to have a protective role against fibrosis and malignancy; therefore, further evaluated its role in our mouse model of chronic pancreatitis. We observed that introduction of recombinant interleukin-15 has indeed improve chronic pancreatitis-associated epithelial-to-mesenchymal transition-mediated development of a malignant phenotype in the mouse model of chronic pancreatitis. In conclusion, we present evidence that rIL-15 overexpression improves eosinophilic inflammation-induced epithelial-to-mesenchymal transition-mediated progression of pancreatic remodeling associated malignant phenotype and acute lung injury by inducing NKT cells and IFN-γ mediated innate immunity in experimental pancreatitis.
患有慢性胰腺炎的患者发生胰腺恶性肿瘤的风险增加，但这种关系的潜在机制尚不清楚。我们通过使用组合的促胰液素和氧化偶氮甲烷对小鼠进行慢性胰腺炎模型治疗。在我们的模型中，我们显示促胰液素和氧化偶氮甲烷处理的小鼠会发展出病理性恶性表型以及相关的肺部炎症。我们观察到慢性胰腺炎相关的促炎细胞因子，如白细胞介素-6、白细胞介素-15 和粒细胞巨噬细胞集落刺激因子的诱导，以及巨噬细胞和嗜酸性粒细胞炎症的积累。我们还观察到嗜酸性粒细胞脱颗粒，胰腺星状细胞激活介导的上皮间质转化相关蛋白，表现出胰腺恶性表型，包括腺泡导管化生和腺泡细胞萎缩。我们观察到高度诱导的白细胞介素-15，它之前被报道具有对抗纤维化和恶性肿瘤的保护作用；因此，我们进一步评估了它在我们的慢性胰腺炎小鼠模型中的作用。我们观察到，重组白细胞介素-15 的引入确实改善了慢性胰腺炎相关的上皮间质转化介导的胰腺重塑相关恶性表型的发展，在慢性胰腺炎的小鼠模型中。总之，我们提供的证据表明，rIL-15 的过表达通过诱导 NKT 细胞和 IFN-γ 介导的固有免疫，改善了嗜酸性粒细胞炎症诱导的上皮间质转化介导的胰腺重塑相关恶性表型和急性肺损伤的进展。
