N-Acetylcysteine Reduces the Pro-Oxidant and Inflammatory Responses during Pancreatitis and Pancreas Tumorigenesis.

Marie-Albane Minati,Mohamad Assi,Patrick Jacquemin,Hajar Dahou,Maxime Libert

doi:10.3390/antiox10071107

Marie-Albane Minati, Mohamad Assi + Show 3 more

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https://doi.org/10.3390/antiox10071107

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Abstract

Pancreatitis, an inflammation of the pancreas, appears to be a main driver of pancreatic cancer when combined with Kras mutations. In this context, the exact redox mechanisms are not clearly elucidated. Herein, we treated mice expressing a KrasG12D mutation in pancreatic acinar cells with cerulein to induce acute pancreatitis. In the presence of KrasG12D, pancreatitis triggered significantly greater redox unbalance and oxidative damages compared to control mice expressing wild-type Kras alleles. Further analyses identified the disruption in glutathione metabolism as the main redox event occurring during pancreatitis. Compared to the wild-type background, KrasG12D-bearing mice showed a greater responsiveness to treatment with a thiol-containing compound, N-acetylcysteine (NAC). Notably, NAC treatment increased the pancreatic glutathione pool, reduced systemic markers related to pancreatic and liver damages, limited the extent of pancreatic edema and fibrosis as well as reduced systemic and pancreatic oxidative damages. The protective effects of NAC were, at least, partly due to a decrease in the production of tumor necrosis factor-α (TNF-α) by acinar cells, which was concomitant with the inhibition of NF-κB(p65) nuclear translocation. Our data provide a rationale to use thiol-containing compounds as an adjuvant therapy to alleviate the severity of inflammation during pancreatitis and pancreatic tumorigenesis.

Highlights

Acute pancreatitis is defined as a transient and local inflammation of the pancreas characterized by immune cell infiltration and edema [1]
Multiple studies have characterized the redox alterations occurring during inflammation-induced metabolic dysfunction and pancreatitis in wild-type rodents [9,10,11,12,13,14,15,16]; there is a lack of information regarding the main redox changes taking place during the initiation of pancreas tumorigenesis
To investigate the main pancreatitis-driven redox changes occurring in the presence of either wild-type Kirsten rat sarcoma (Kras) or mutated KrasG12D alleles, WT and Ela-KrasG12D mice were challenged with cerulein for 5 days to induce pancreatitis

Summary

Introduction

Acute pancreatitis is defined as a transient and local inflammation of the pancreas characterized by immune cell infiltration and edema [1]. Multiple studies have characterized the redox alterations occurring during inflammation-induced metabolic dysfunction and pancreatitis in wild-type rodents [9,10,11,12,13,14,15,16]; there is a lack of information regarding the main redox changes taking place during the initiation of pancreas tumorigenesis (presence of Kras mutations). To fill this gap of knowledge in the field, we compared mice expressing Kras wild-type alleles (control mice) with those expressing acinar-specific mutated KrasG12D oncogenic allele. We found that pancreatitis induced greater redox unbalance and oxidative damages during pancreas tumorigenesis in mice bearing KrasG12D

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