Activin in acute pancreatitis: Potential risk-stratifying marker and novel therapeutic target

Jonas J Staudacher,Yinglin Xia,Claudia Kunst,Jessica Bauer,Jingbo Pang,Timothy Carroll,Georgios Papachristou,Andrea Dirmeier,Barbara Jung,Cemal Yazici,Nancy Krett,David C Whitcomb,Annette Wilson,Giamila Fantuzzi

doi:10.1038/s41598-017-13000-3

Abstract

Acute Pancreatitis is a substantial health care challenge with increasing incidence. Patients who develop severe disease have considerable mortality. Currently, no reliable predictive marker to identify patients at risk for severe disease exists. Treatment is limited to rehydration and supporting care suggesting an urgent need to develop novel approaches to improve standard care. Activin is a critical modulator of inflammatory responses, but has not been assessed in pancreatitis. Here, we demonstrate that serum activin is elevated and strongly correlates with disease severity in two established murine models of acute pancreatitis induced by either cerulein or IL-12 + IL-18. Furthermore, in mice, inhibition of activin conveys survival benefits in pancreatitis. In addition, serum activin levels were measured from a retrospective clinical cohort of pancreatitis patients and high activin levels in patients at admission are predictive of worse outcomes, indicated by longer overall hospital and intensive care unit stays. Taken together, activin is a novel candidate as a clinical marker to identify those acute pancreatitis patients with severe disease who would benefit from aggressive treatment and activin may be a therapeutic target in severe acute pancreatitis.

Highlights

Acute Pancreatitis is a substantial health care challenge with increasing incidence
Since activin is increased in animals after sham-operations[29,30], we used a non-invasive induced model of Acute Pancreatitis (AP), in which IP injections of IL-12 + IL-18 on subsequent days lead to aggressive necrotizing AP in ob/ob mice and a mild, edematous pancreatitis in wild-type animals
We measured an array of cytokines critical in the inflammatory response in AP and observed cytokine patterns similar to those reported in human disease with marked increases in IL-6, IL-10, interferon-gamma and tumor necrosis factor (TNF) confirming the applicability of our model

Summary

Introduction

Acute Pancreatitis is a substantial health care challenge with increasing incidence. Patients who develop severe disease have considerable mortality. We demonstrate that serum activin is elevated and strongly correlates with disease severity in two established murine models of acute pancreatitis induced by either cerulein or IL-12 + IL-18. Activin is a novel candidate as a clinical marker to identify those acute pancreatitis patients with severe disease who would benefit from aggressive treatment and activin may be a therapeutic target in severe acute pancreatitis. Severe pancreatitis, defined by current guidelines[3,4] as persistent organ failure for more than 48 hours, is associated with high mortality rates in the range of 15–20%5, partly due to limited therapeutic options[3]. Plays in these conditions, we hypothesized that activin may be upregulated in AP, and constitute a potential marker of disease severity or a novel therapeutic target

Methods

Results

Conclusion