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.

Introduction

Exocrine pancreatic insufficiency (EPI) following acute pancreatitis (AP) has been reported heterogeneously with unclear recovery timeline.

Aims & Methods

Aim: To determine the prevalence of EPI after AP and the prevalence and predictors of persistent EPI after AP for at least 6 months.
Methods: Prospective longitudinal study of consecutive adult patients diagnosed with first episode of AP. Excluded patients with previous EPI, follow-up after AP <12months and after EPI <6months. EPI was assessed by elastase fecal-1 and endocrine pancreatic insufficiency (EnPI) by fasting serum glucose, HbA1c and oral glucose tolerance test. Patients with AP who developed EPI were randomized to receive pancreatic enzyme replacement therapy (PERT, 4000IU with each meal and 20000IU with snacks; clinicaltrials.gov NCT05480241) vs. placebo. Clinical, inflammatory, nutritional and immunological factors were evaluated. Evaluated predictors for persistent EPI (≥6months) and compared with transient EPI (<6months) and AP with no EPI groups.

Results

A total of 105 patients (65.7%(n=69) males; mean age:63.8±17.1yo) were enrolled and followed-up, 65.7% with alcoholic/biliary etiology. AP was moderately-severe in 32.4% and severe in 16.2%. EPI (mean elastase fecal-1 176.9±175.8 (vs. 425.1±105.0; p<0.001) was observed in 50 (47.6%) patients, being severe in 60% and 38% of patients with mild AP: 64% at the time, 14% at 1 month, 16% at 3 months and 6% at 6 months of AP diagnosis. EnPI was diagnosed in 17.1%(n=18) and 19.0%(n=20) has previous diabetes mellitus. EPI was persistent (≥6 months after EPI diagnosis) in 58%(n=29; mean elastase fecal-1 83.8±58.5 (vs. 373.6±118.4; p<0.001)), being 31%(n=9) with mild AP. 6-month post-randomization, 44%(n=11/25) under PERT and 40%(n=10/25) under placebo resolved EPI (p=0.598), with statically significance for severe EPI (resolved EPI: PERT-20%; placebo-12%; p=0.04).
After univariate/multivariate analysis, factors significantly associated with persistent EPI were previous diabetes (OR 15.382; p=0.001), EnPI (OR 9.906; p=0.042), recurrent AP (OR 7.182; p=0.028), non-biliary etiology (OR 5.744; p=0.037), increasing AP severity (OR 21.386; p<0.001), mMarshal score ≥2 (OR 23.026; p=0.001), intermediate/intensive care unit admission (OR 19.583; p=0.003), pancreatic necrosis (OR 21.05; p=0.007) and low magnesium (OR 45.690; p=0.045).

Conclusion

EPI following AP is a non-negligible condition, present in almost half of patients during first 6months after AP diagnosis, being severe in about 2/3 of patients and persists for at least 6 months in more than half of patients, Previous diabetes, EnPI, recurrent AP, non-biliary etiology, severe AP and low magnesium were strongly and independent associated with persistent PEI. Since can occur and be persistent even in mild AP, is crucial understand injury mechanisms, stratify patient’s risk, tailoring screening and start PERT early.

References

1. Phillips AE, Beijani J, Culp S, Chennat J, Lee PJ, Machicado JD, et al. Prevalence of exocrine pancreatic insufficiency at 12 months after acute pancreatitis: a prospective, multicentre, longitudinal cohort study. E Clinical Medicine 2024;75:102774.
2. Huang W, de la Iglesia-García D, Baston-Rey I, Calviño-Suarez C, Lariño-Noia J, Iglesias-Garcia J, et al. Exocrine pancreatic insufficiency following acute pancreatitis: Systematic review and meta-analysis. Dig Dis Sci 2019;64(7):1985-2005.
3. Jawaid S, Forsmark CE. Exocrine pancreatic insufficiency following acute pancreatitis: true association or EPIphenomenon?. Dig Dis Sci 2019;67(7):1731-1733.