Nox 1-Evoked Ros Causes Fibrosis in Caerulein-Induced Chronic Pancreatitis Through the Akt Pathway

Abstract

Chronic pancreatitis (CP) manifests from a long-term inflammation, resulting in significant fibrosis of the pancreatic tissue and permanent organ damage. This occurs due to pro-inflammatory mediators, including reactive oxygen species (ROS). One of the sources of ROS is NADPH oxidase (Nox) enzymes, which transfer electrons across biological membranes to reduce oxygen to superoxide. The rodent genome encodes four Nox enzymes: Nox 1-4. We found that Nox 1 is implicated in pancreatic fibrogenesis in a mouse model of CP. Our next goal was to determine which intracellular pathway mediates the effect of Nox1-derived ROS. Several intracellular pathways are activated following Nox1-derived ROS, including JNK, AKT, and ERK1/2. Each pathway is also activated following caerulein, a cholecystokinin analogue. Our hypothesis was that repetitive administration of caerulein stimulates Nox1-derived ROS, which causes increased oxidative stress, leading to fibrogenesis through phosphorylation of ERK, AKT and JNK. We found the lack of Nox1 impaired the phosphorylation of AKT in a mouse model of CP. In conclusion, Nox1 mediates fibrogenesis through the AKT pathway in mice with CP.