Protective Effects of Necrostatin-1 in Acute Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1

Abstract

Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1K45A: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1K45A were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1K45A modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca2+ entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important.

Understanding Necroptosis in Pancreatic Diseases

“…Multiple studies have unraveled that Nec-1 is effective at inducing AP. However, RIPK1 kinase modification (RIPK1K45A: kinase-dead) only functions in some mice models, indicating that RIPK1 may play a secondary role in mediating necroptosis [ 95 ]. Later on, other studies also exposed that, when activated RIPK1 in acinar cells is inhibited, AP mice might mediate RIPK1-dependent necrotizing regulation through the RIPK1/NF-κB/AQP8 axis, thereby regulating the changes in the degree of local and systemic inflammation [ 96 ].…”

Latest in Cellular Pathology Research

“…Ouyang et al [ 9 ] focused on acute pancreatitis (AP), a severe and potentially fatal disease caused predominantly by the formation of gallstones or excessive alcohol consumption. In 4 out of 5 cases, AP improves quickly and does not cause serious problems; however, 1 in 5 cases becomes severe and can result in life-threatening complications.…”