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.
Highlights
Acute pancreatitis (AP) is a painful, debilitating inflammatory disease with significant mortality
Consistent with histological data, the effects of RIPK1K45A on biochemical parameters did not reflect those of pharmacological inhibition, with either no or partial inhibition observed in the AP models
RIPK1K45A only partially decreased the former in taurolithocholic acid sulphate (TLCS)-AP and CER-AP, with no effect in FAEE-AP (Figure 2c) and was without effect on raised lung MPO levels in all models (Figure 2d)
Summary
Acute pancreatitis (AP) is a painful, debilitating inflammatory disease with significant mortality. Core to the development of AP is damage to exocrine tissue, with extensive parenchymal necrosis that determines clinical outcome; in severe cases a systemic inflammatory response syndrome (SIRS), multiple organ failure and patient death may ensue. Necroptosis, a programmed form of necrosis, has the same endpoint as necrosis but is differentiated by integral activation of receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). It constitutes a regulated cell death programme in response to activation of death receptors, Toll- and NOD-like receptors, T cell receptors, genotoxic stress and viruses [6]. RIPK1 involvement has been shown in necroptosis-associated disease, including myocardial infarction, stroke, neurodegeneration and ischaemia-reperfusion injury [7,8,9]
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