Chronic inflammation promotes epithelial-mesenchymal transition-mediated malignant phenotypes and lung injury in experimentally-induced pancreatitis.

Abstract

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.

• Authors: Hemanth Kumar Kandikattu, Murli Manohar, Sathisha Upparahalli Venkateshaiah, Chandrasekhar Yadavalli, Anil Mishra
• Journal: Life sciences (Life Sci) Vol. 278 Pg. 119640 (Aug 01 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 34048812 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Topics

• Animals
• Chronic Disease
• Disease Models, Animal
• Epithelial-Mesenchymal Transition
• Female
• Inflammation (complications, pathology)
• Lung Injury (etiology, pathology)
• Male
• Mice, Inbred BALB C
• Pancreas (pathology)
• Pancreatic Neoplasms (etiology, pathology)
• Pancreatitis, Chronic (etiology, pathology)
• Mice