Phellodendrine alleviates acute pancreatitis by inhibiting p38 MAPK-p47phox pathway-mediated neutrophil extracellular traps formation and ROS production

Background: Acute pancreatitis (AP) is an inflammatory disorder of pancreas, where the formation of neutrophil extracellular traps (NETs) plays a crucial role in its pathogenesis. This study examined the therapeutic effect of Phellodendrine (PHE), a Phellodendron-derived alkaloid, on AP by assessing NETs formation and underlying mechanisms.

Methods: Mouse bone marrow neutrophils were isolated and stimulated to form NETs in vitro to assess PHE's impact. A Caerulein-induced AP mouse model was developed to assess the in vivo efficacy of PHE. Network pharmacology and RNA-seq analysis were utilized to investigate the mechanisms through which PHE alleviates AP. The functional role of the identified target was verified using a p38 inhibitor.

Results: PHE markedly inhibited NETs formation and Reactive Oxygen Species (ROS) generation in vitro. In vivo experiments further revealed PHE treatment alleviated pancreatic injury and inflammation, which was accompanied by reduced NETs formation and neutrophil infiltration in the mouse of AP. Mechanistically, PHE targeted the p38 MAPK pathway, suppressing its activation and the subsequent membrane translocation of p47^phox. Furthermore, co-administration with a p38 inhibitor abolished the inhibitory effects of PHE on NETs formation and ROS production.

Conclusion: PHE mitigates pancreatic injury and inflammation in AP through its inhibitory effect on NETs formation and ROS production, mediated by targeting the p38 MAPK-p47^phox pathway. This indicates its potential as an innovative therapeutic agent for the treatment of AP.

Acute pancreatitis; MAPK; Neutrophil extracellular traps; Phellodendrine; Reactive oxygen species.