Introduction

Chronic pancreatitis (CP) is a multifactorial, inflammatory disease characterized by progressive destruction of the pancreas, with fibrotic transformation of the tissue as a major morphological feature. The incidence of the disease is steadily increasing, but no specific therapy is currently available, making the identification of new therapeutic targets a priority. Plasminogen activator inhibitor-1 (PAI-1, encoded by SERPINE1) has been implicated in various pathological processes, including fibrosis and inflammation. However, its specific involvement in the pathogenesis of CP is not yet fully understood.

Aims & Methods

We therefore aimed to explore the role of PAI-1 in the development of CP and assess the therapeutic potential of PAI-1 inhibitors as antifibrotic agents to prevent the progression of CP.
​The PAI-1 expression was measured in human pancreatic tissue samples with immunohistochemistry, and human blood serum with ELISA. CP was induced in FVB/N mice with intraperitoneal cerulein injections given every hour, every 3 days for a total of 5 times. PAI-1 activity was inhibited with a specific inhibitor, which was administered per os at a dose of 10 mg/kgbw for 6 consecutive days after the 3rd cerulein treatment. Inflammation and fibrosis were assessed using hematoxylin-eosin and Crossman’s trichrome staining, while biochemical assays measured amylase activity and hydroxyproline concentration. SERPINE1 gene expression was quantified using RT-qPCR, and PAI-1 protein levels and localization were assessed via immunohistochemistry and immunofluorescence co-staining. In vitro, pancreatic fibroblast cells isolated from CP mice were treated with a 10 μM PAI-1 inhibitor.

Results

PAI-1 levels were significantly elevated in both pancreatic tissue and blood samples obtained from CP patients. In CP-induced mice, the body weight and the pancreatic weight/body weight ratio significantly reduced, while histopathology showed significant pancreatic atrophy and fibrosis. This was also confirmed by the increased hydroxyproline concentration and decreased amylase activity of the pancreatic tissue. SERPINE1 gene expression was upregulated in pancreatic tissue and fibroblast cultures in the CP group, while PAI-1 protein levels were elevated in pancreatic tissue. The elevated PAI-1 signal localization and the high overlap with vimentin suggests a possible expression role for activated pancreatic stellate cells (PSC). Administration of a PAI-1 inhibitor reduced body weight and pancreatic weight loss rates, along with significant decreases in pancreatic atrophy, fibrosis, hydroxyproline concentrations, and SERPINE1 gene expression compared to the CP group. In vitro, PAI-1 inhibition reduced cell migration rate and SERPINE1 gene expression in PSC derived from CP mice.

Conclusion

Our results indicate an elevation in PAI-1 expression in CP, with the potential for fibrosis and tissue atrophy reduction by the inhibition of PAI-1. These findings propose PAI-1 as a promising therapeutic target for the treatment of chronic pancreatitis.