Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
Endocr Metab Immune Disord Drug Targets. 2023;23(10):1303-1317. doi: 10.2174/1871530322666220804104224.
Develop a novel murine models of malignant pancreatitis.
Although patients with chronic pancreatitis are at a greater risk of developing pancreatic cancer, there is no definitive mouse model that currently develops chronic pancreatitis-induced pancreatic cancer.
Characterization of eosinophilic inflammation-mediated malignant pancreatitis in novel murine model.
We developed a murine model of chronic eosinophilic inflammation associated with pancreatitis that also shows characteristic features of pancreatic malignancy. The mouse received cerulein and azoxymethane via intraperitoneal administration developed pathological malignant phenotype, as well as concomitant lung inflammation.
We discovered pathological alterations in the pancreas that were associated with chronic pancreatitis, including a buildup of eosinophilic inflammation. Eosinophil degranulation was reported nearby in the pancreas tissue sections that show acinar-to-ductal metaplasia and acinar cell atrophy, both of which are characteristic of pancreatic malignancies. Additionally, we also observed the formation of PanIN lesions after three initial doses of AOM and eight weeks of cerulein with the AOM treatment regimen. We discovered that persistent pancreatic eosinophilic inflammation linked with a pancreatic malignant phenotype contributes to pulmonary damage. The RNA seq analysis also confirmed the induction of fibro-inflammatory and oncogenic proteins in pancreas and lung tissues. Further, in the current manuscript, we now report the stepwise kinetically time-dependent cellular inflammation, genes and proteins involved in the development of pancreatitis malignancy and associated acute lung injury by analyzing the mice of 3 AOM with 3, 8, and 12 weeks of the cerulein challenged protocol regime.
We first show that sustained long-term eosinophilic inflammation induces time-dependent proinflammatory, profibrotic and malignancy-associated genes that promote pancreatic malignancy and acute lung injury in mice.
建立一种新型的恶性胰腺炎小鼠模型。
尽管慢性胰腺炎患者发生胰腺癌的风险更高，但目前尚无明确的可诱发慢性胰腺炎相关胰腺癌的小鼠模型。
描述新型小鼠模型中嗜酸性粒细胞炎症介导的恶性胰腺炎。
我们开发了一种与胰腺炎相关的慢性嗜酸性粒细胞炎症的小鼠模型，该模型还表现出胰腺恶性肿瘤的特征。通过腹腔内给予蛙皮素和氧化偶氮甲烷，小鼠发展出病理性恶性表型，并伴有肺部炎症。
我们发现胰腺的病理性改变与慢性胰腺炎相关，包括嗜酸性粒细胞炎症的积聚。在胰腺组织切片中，嗜酸性粒细胞脱颗粒被报道在腺泡到导管的化生和腺泡细胞萎缩附近，这两者都是胰腺恶性肿瘤的特征。此外，我们还观察到在用 AOM 进行三次初始剂量和用 AOM 治疗方案进行八周的蛙皮素后，形成 PanIN 病变。我们发现持续的胰腺嗜酸性粒细胞炎症与胰腺恶性表型相关，导致肺部损伤。RNA 测序分析还证实了胰腺和肺组织中纤维化炎症和致癌蛋白的诱导。此外，在本研究中，我们现在报告通过分析接受 3 次 AOM 和 3、8 和 12 周蛙皮素挑战方案的小鼠，逐步阐明涉及胰腺炎恶性肿瘤和相关急性肺损伤发展的细胞炎症、基因和蛋白质的时变动力学。
我们首次表明，持续的长期嗜酸性粒细胞炎症诱导时间依赖性促炎、促纤维化和与恶性相关的基因，促进小鼠的胰腺恶性肿瘤和急性肺损伤。
