Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models.

Ejas Palathingal Bava,Tejeshwar Jain,Harrys K C Jacob,Preeti Sahay,Anthony Ferrantella,John George,Beatriz Gomez Aguilar,Utpreksha Vaish,Ashok K Saluja,Prateek Sharma,Craig L Maynard,Srikanth Iyer,Dujon B Edwards,Rajinder K Dawra,Bhuwan Giri,Mohammad Tarique,Vrishketan Sethi,Vikas Dudeja

doi:10.1172/jci.insight.141108

Abstract

Despite decades of research, there is no specific therapy for acute pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an antiinflammatory and antifibrotic agent that is approved by the FDA for treatment of idiopathic pulmonary fibrosis (IPF), in ameliorating local and systemic injury in AP. Our results suggest that treatment with pirfenidone in therapeutic settings (e.g., after initiation of injury), even when administered at the peak of injury, reduces severity of local and systemic injury and inflammation in multiple models of AP. In vitro evaluation suggests that pirfenidone decreases cytokine release from acini and macrophages and disrupts acinar-macrophage crosstalk. Therapeutic pirfenidone treatment increases IL-10 secretion from macrophages preceding changes in histology and modulates the immune phenotype of inflammatory cells with decreased levels of inflammatory cytokines. Antibody-mediated IL-10 depletion, use of IL-10–KO mice, and macrophage depletion experiments confirmed the role of IL-10 and macrophages in its mechanism of action, as pirfenidone was unable to reduce severity of AP in these scenarios. Since pirfenidone is FDA approved for IPF, a trial evaluating the efficacy of pirfenidone in patients with moderate to severe AP can be initiated expeditiously.

Highlights

Acute pancreatitis (AP), a common gastrointestinal (GI) disorder, is one of the most common causes of hospitalization due to a GI disease in the United States [1]
To further substantiate our finding that the mechanism of pirfenidone action is through increased IL10 release from macrophages at 110h time point, that paves the way for alleviation of local and systemic injury in pancreatitis, we demonstrate that the salutary effects of pirfenidone are abrogated either in absence of IL10 (IL10-Knock Out [KO] mice) or reparative M2 macrophages
We have demonstrated that pirfenidone, an anti-fibrotic, antioxidant and anti-inflammatory drug that is FDA approved for the treatment of idiopathic pulmonary fibrosis, is effective in decreasing the severity of AP in multiple animal models of this disease

Summary

Introduction

Acute pancreatitis (AP), a common gastrointestinal (GI) disorder, is one of the most common causes of hospitalization due to a GI disease in the United States [1]. Pathogenesis of AP can be broadly divided into two phases: an early intra-acinar initiation phase and a later phase of local and systemic inflammation. By the time patients with AP present to the hospital, the intra-acinar events have already transpired, and the disease has typically advanced to the stage of local and systemic inflammation. As a result, targeting early intra-acinar events, for instance protease activation [4, 5], has not resulted in improved outcomes in AP. Apart from select few clinical settings, where it may be feasible to target intra-acinar events for therapeutic benefit (for instance prevention of ERCP induced AP and prevention of recurrent AP), specific treatment for AP will emerge from strategies addressing local and systemic inflammation [3]

Methods

Results

Conclusion