Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models.

BACKGROUND

Acute pancreatitis (AP) encompasses a spectrum of pancreatic inflammatory conditions, ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure. Given the challenges associated with obtaining human pancreatic samples, research on AP predominantly relies on animal models. In this study, we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models.

AIM

To investigate the shared molecular changes underlying the development of AP across varying severity levels.

METHODS

AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide (LPS). Additionally, using to drive the specific expression of the promoter in pancreatic acinar cells transgenic C57BL/6J- mice were administered Clozapine N-oxide to induce AP. Subsequently, we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus (GEO) database.

RESULTS

Caerulein-induced AP showed severe inflammation and edema, which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis. Compared with the control group, RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the and -like receptor signaling pathway, TLR signaling pathway, and signaling pathway, alongside elevated levels of apoptosis-related pathways, such as apoptosis, pathway, and phagosome pathway. The significantly elevated genes in the and -like receptor signaling pathways, as well as in the apoptosis pathway, were validated through quantitative real-time PCR experiments in animal models. Validation from the GEO database revealed that only concurred in both mouse pancreatic tissue and human AP peripheral blood, while , , , and genes exhibited marked elevation in human AP. The genes and played significant roles in apoptosis within human AP. The transgenic mouse model successfully validated significant differential genes in the and -like receptor signaling pathways as well as the apoptosis pathway, indicating that these pathways represent shared pathological processes in AP across different models.

CONCLUSION

The and receptor signaling pathways play crucial roles in the inflammatory progression of AP, notably the gene. Apoptosis holds a central position in the necrotic processes of AP, with and genes exhibiting prominence in human AP.