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

Bombardo, M, Malagola, E, Chen, R, Rudnicka, A, Graf, R and Sonda, S ORCID: 0000-0001-8152-3425 2018 , 'Ibuprofen and diclofenac treatments reduce proliferation of pancreatic acinar cells upon inflammatory injury and mitogenic stimulation' , British Journal of Pharmacology, vol. 175, no. 2 , pp. 335-347 , doi: 10.1111/bph.13867.

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Abstract

BACKGROUND AND PURPOSE:Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered to manage the pain typically found in patients suffering frompancreatitis. NSAIDs also display anti-proliferative activity against cancer cells; however, their effects on normal, untransformedcells are poorly understood. Here, we evaluated whether NSAIDs inhibit the proliferation of pancreatic acinar cells during thedevelopment of acute pancreatitis.EXPERIMENTAL APPROACH:The NSAIDs ibuprofen and diclofenac were administered to C57BL/6 mice after induction of pancreatitis with serial injections ofcerulein. In addition, ibuprofen was administered concomitantly with 3,5,3-L-tri-iodothyronine (T3), which induces acinar cellproliferation in the absence of tissue inflammation. The development of pancreatic inflammation, acinar de-differentiation intometaplastic 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 M1macrophage polarization and pro-inflammatory cytokine expression both in vivo and in vitro. Reduced macrophage activationwas accompanied by reduced acinar de-differentiation into acinar-to-ductal metaplasia. Acinar proliferation was significantlyimpaired in the presence of ibuprofen and diclofenac, as demonstrated at both the level of proliferation markers and expression ofcell cycle regulators. Ibuprofen also reduced acinar cell proliferation induced by mitogenic stimulation with T3, a treatment thatdoes not elicit pancreatic inflammation.CONCLUSIONS AND IMPLICATIONS:Our study provides evidence that the NSAIDs ibuprofen and diclofenac inhibit pancreatic acinar cell division. This suggests thatprolonged treatment with these NSAIDs may negatively affect the regeneration of the pancreas and further studies are needed toconfirm these findings in a clinical setting.

Item Type: Article
Authors/Creators:Bombardo, M and Malagola, E and Chen, R and Rudnicka, A and Graf, R and Sonda, S
Keywords: NSAIDs, pancreatitis
Journal or Publication Title: British Journal of Pharmacology
Publisher: Nature Publishing Group
ISSN: 0007-1188
DOI / ID Number: 10.1111/bph.13867
Copyright Information:

© 2017 The British Pharmacological Society

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