Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models
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 loc...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-01-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.141108 |
| _version_ | 1811334806878814208 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ejas Palathingal Bava |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T17:14:34Z |
| format | Article |
| id | doaj.art-5a67edc6225d42e6a846bf7637ca2d15 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T17:14:34Z |
| publishDate | 2022-01-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-5a67edc6225d42e6a846bf7637ca2d152022-12-22T02:38:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-01-0172Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine modelsEjas Palathingal BavaJohn GeorgeMohammad TariqueSrikanth IyerPreeti SahayBeatriz Gomez AguilarDujon B. EdwardsBhuwan GiriVrishketan SethiTejeshwar JainPrateek SharmaUtpreksha VaishHarrys K. C. JacobAnthony FerrantellaCraig L. MaynardAshok K. SalujaRajinder K. DawraVikas DudejaDespite 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.https://doi.org/10.1172/jci.insight.141108GastroenterologyInflammation |
| spellingShingle | 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 Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models JCI Insight Gastroenterology Inflammation |
| title | Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models |
| title_full | Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models |
| title_fullStr | Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models |
| title_full_unstemmed | Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models |
| title_short | Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models |
| title_sort | pirfenidone increases il 10 and improves acute pancreatitis in multiple clinically relevant murine models |
| topic | Gastroenterology Inflammation |
| url | https://doi.org/10.1172/jci.insight.141108 |
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