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

• Published in: British journal of pharmacology 2018-01, Vol.175 (2), p.335-347
• Main Authors: Bombardo, Marta, Malagola, Ermanno, Chen, Rong, Rudnicka, Alina, Graf, Rolf, Sonda, Sabrina
• Format: Article
• Language: English
• Subjects: Acinar cells; Acinar Cells - cytology; Acinar Cells - drug effects; Acinar Cells - pathology; Animals; Anti-inflammatory agents; Cancer; Cell activation; Cell cycle; Cell Differentiation - drug effects; Cell division; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Ceruletide; Cytokines - metabolism; Diclofenac; Diclofenac - pharmacology; Diclofenac - therapeutic use; Ibuprofen; Ibuprofen - pharmacology; Ibuprofen - therapeutic use; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Lesions; Macrophages; Male; Metaplasia; Mice; Mitogens - pharmacology; Neutrophil Infiltration - drug effects; Nonsteroidal anti-inflammatory drugs; Pain; Pancreas; Pancreas - cytology; Pancreas - drug effects; Pancreas - pathology; Pancreatitis; Pancreatitis - chemically induced; Pancreatitis - drug therapy; Pancreatitis - pathology; Polymerase chain reaction; Research Paper; Stimulation; Themed Section: Research Papers; Triiodothyronine - antagonists & inhibitors; Triiodothyronine - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13867

Background and Purpose Nonsteroidal 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 Approach The 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 Results Therapeutic 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 Implications Our 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 Articles This 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