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Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models
Ejas Palathingal Bava, … , Rajinder K. Dawra, Vikas Dudeja
Ejas Palathingal Bava, … , Rajinder K. Dawra, Vikas Dudeja
Published November 30, 2021
Citation Information: JCI Insight. 2022;7(2):e141108. https://doi.org/10.1172/jci.insight.141108.
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Research Article Gastroenterology Inflammation

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

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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.

Authors

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

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Figure 1

Therapeutic pirfenidone administration reduces local pancreatic injury and lung injury in caerulein 2-day model of acute pancreatitis.

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Therapeutic pirfenidone administration reduces local pancreatic injury a...
(A) Schematic of therapeutic administration of pirfenidone in a caerulein 2-day model of acute pancreatitis. (B) Representative histology (H&E, 100×) and histological analysis of pancreatic histology from AP-only group and pirfenidone-treated group. Therapeutic pirfenidone treatment leads to a decrease in pancreatic edema, necrosis, and inflammatory infiltrates. Histologic quantification of edema, necrosis, and inflammation is also shown. (C) Serum amylase levels were significantly decreased in the pirfenidone treatment group. (D) IHC for coronin 1A (200×), which stains leukocytes, shows a decrease in immune cell infiltration with pirfenidone treatment. Pancreatic MPO, which is a marker of neutrophilic infiltration, also shows a significant decrease with treatment. (E) Pancreas wet/dry weight ratio, a measure of pancreatic edema, shows a significant decrease in the pirfenidone-treatment group. (F and G) Serum HMGB1 and serum CRP, biomarkers that correlate with severity of AP, were significantly reduced with therapeutic pirfenidone treatment. (H) Lung H&E (100×) shows a reduction in injury with treatment. (I) IHC of lung sections for coronin 1A (200×) shows a decrease in immune infiltration with pirfenidone treatment. Lung MPO (myeloperoxidase) also shows a significant decrease with treatment. (J) Lung wet/dry weight ratio (a measure of pulmonary edema) shows a significant decrease in the treatment group. Pirf., pirfenidone. n = 8 each in AP-only and AP + pirf group. n = 5 each in control groups in F and G. Data represent mean ± SEM. *P < 0.05 by Mann-Whitney U test for B–E, I, and J and Kruskal-Wallis test (Dunn’s multiple-comparison test) for F and G.

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