Development and Characterization of Novel Chronic Eosinophilic Inflammation-Mediated Murine Model of Malignant Pancreatitis

Abstract

Aims: Development and characterization of novel chronic eosinophilic inflammation-mediated murine model of malignant pancreatitis Background: Despite the fact that patients with chronic pancreatitis are at a greater risk of developing pancreatic cancer, there is no definitive mouse model that develops chronic pancreatitis-induced pancreatic cancer currently. Objective: Development and characterization of novel chronic eosinophilic inflammation-mediated murine model of malignant pancreatitis Method: We developed a chronic eosinophilic inflammation associated pancreatitis murine model that show characteristic features of pancreatic malignancy. The model was developed by administering intraperitoneally mixture of cerulein and azoxymethane to mice that demonstrate that mice treated with cerulein and azoxymethane (AOM) develop a pathological malignant phenotype, as well as concomitant lung inflammation. Result: 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 3 initial doses of AOM and 8 weeks of cerulein with 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 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 lug injury by analyzing the mice of 3 AOM with 3, 8, and 12 weeks of cerulein challenged protocol regime. Conclusion: Taken together, we first time show that sustain long term eosinophilic inflammation induces time and dose dependent proinflammatory, profibrotic and malignancy associated genes that promote pancreatic malignancy associated acute lung injury in mice.