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journal article Jun 16, 2017

Ibuprofen and diclofenac treatments reduce proliferation of pancreatic acinar cells upon inflammatory injury and mitogenic stimulation

Marta Bombardo Ermanno Malagola ORCID Rong Chen ORCID Alina Rudnicka Rolf Graf ORCID Sabrina Sonda ORCID
British Journal of Pharmacology Vol. 175 No. 2 pp. 335-347 · Wiley
View at Publisher Save 10.1111/bph.13867
Abstract
Background and PurposeNonsteroidal anti‐inflammatory drugs (NSAIDs) are administered to manage the pain typically found in patients suffering from pancreatitis. NSAIDs also display anti‐proliferative activity against cancer cells; however, their effects on normal, untransformed cells are poorly understood. Here, we evaluated whether NSAIDs inhibit the proliferation of pancreatic acinar cells during the development of acute pancreatitis.Experimental ApproachThe NSAIDs ibuprofen and diclofenac were administered to C57BL/6 mice after induction of pancreatitis with serial injections of cerulein. In addition, ibuprofen was administered concomitantly with 3,5,3‐L‐tri‐iodothyronine (T3), which induces acinar cell proliferation in the absence of tissue inflammation. The development of pancreatic inflammation, acinar de‐differentiation into metaplastic lesions and acinar proliferation were quantified by histochemical, biochemical and RT‐PCR approaches.Key ResultsTherapeutic ibuprofen treatment selectively reduced pancreatic infiltration of activated macrophages in vivo, and M1 macrophage polarization and pro‐inflammatory cytokine expression both in vivo and in vitro. Reduced macrophage activation was accompanied by reduced acinar de‐differentiation into acinar‐to‐ductal metaplasia. Acinar proliferation was significantly impaired in the presence of ibuprofen and diclofenac, as demonstrated at both the level of proliferation markers and expression of cell cycle regulators. Ibuprofen also reduced acinar cell proliferation induced by mitogenic stimulation with T3, a treatment that does not elicit pancreatic inflammation.Conclusions and ImplicationsOur study provides evidence that the NSAIDs ibuprofen and diclofenac inhibit pancreatic acinar cell division. This suggests that prolonged treatment with these NSAIDs may negatively affect the regeneration of the pancreas and further studies are needed to confirm these findings in a clinical setting.Linked ArticlesThis article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc
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63
References
Details
Published
Jun 16, 2017
Vol/Issue
175(2)
Pages
335-347
License
View
Authors
M
Marta Bombardo

Swiss Hepato‐Pancreato‐Biliary Center, Department of Visceral and Transplantation Surgery University Hospital of Zurich Zurich Switzerland

E
Ermanno Malagola

Swiss Hepato‐Pancreato‐Biliary Center, Department of Visceral and Transplantation Surgery University Hospital of Zurich Zurich Switzerland

R
Rong Chen

Swiss Hepato‐Pancreato‐Biliary Center, Department of Visceral and Transplantation Surgery University Hospital of Zurich Zurich Switzerland

A
Alina Rudnicka

Swiss Hepato‐Pancreato‐Biliary Center, Department of Visceral and Transplantation Surgery University Hospital of Zurich Zurich Switzerland

R
Rolf Graf

Swiss Hepato‐Pancreato‐Biliary Center, Department of Visceral and Transplantation Surgery University Hospital of Zurich Zurich Switzerland; Center for Integrative Human Physiology (ZIHP) University of Zurich Zurich Switzerland

S
Sabrina Sonda

Swiss Hepato‐Pancreato‐Biliary Center, Department of Visceral and Transplantation Surgery University Hospital of Zurich Zurich Switzerland; Center for Integrative Human Physiology (ZIHP) University of Zurich Zurich Switzerland; Biomedical Science, School of Health Sciences, Faculty of Health University of Tasmania, Newnham Campus Launceston TAS Australia

Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung Award: 310030–146725
Cite This Article
Marta Bombardo, Ermanno Malagola, Rong Chen, et al. (2017). Ibuprofen and diclofenac treatments reduce proliferation of pancreatic acinar cells upon inflammatory injury and mitogenic stimulation. British Journal of Pharmacology, 175(2), 335-347. https://doi.org/10.1111/bph.13867
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