Background: Current severe acute pancreatitis (SAP) murine models face significant limitations. The sodium taurocholate method consistently induces pancreatic necrosis but demands intricate surgical procedures, leading to high variability and infection risks. In contrast, the arginine approach causes acinar cell damage without fully mimicking clinical injury pathways. Furthermore, the caerulein-lipopolysaccharide (CAE-LPS) model, while operationally straightforward, fails to replicate persistent organ failure due to LPS's rapid clearance, thereby inadequately capturing the lethal trajectory observed in clinical SAP patients who succumb to the disease.
Aims: To address these gaps, we developed a SAP mouse model by integrating two key pathogenic mechanisms: trypsin-driven complement activation and sustained complement hyperactivation as drivers of multiple organ failure.
Methods: The SAP model was established by combining CAE-induced pancreatic injury with zymosan (ZYM)-mediated complement activation. Dosing and combination protocols were meticulously optimized and were followed by a comprehensive longitudinal analysis during the acute phase (0-12 days), with comparisons to the CAE-LPS model.
Results: The optimized protocol involved nine intraperitoneal CAE injections (100 μg/kg each) followed by a single ZYM dose (1000 mg/kg). This regimen triggered pancreatic necrosis, inflammatory infiltration, and multi-organ damage (liver, kidney, intestine). Notably, the model demonstrated sustained complement activation and a mortality pattern in non-survivors that more closely aligned with clinical SAP outcomes than the CAE-LPS model.
Conclusion: This novel model offers a robust platform for advancing SAP research, bridging the divide between preclinical studies and clinical translation.
Keywords: Caerulein; Complement cascade; LPS; Multi-organ failure; Serve acute pancreatitis; Zymosan.
© 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.