Role of proteinase-activated receptors 1 and 2 in nonsteroidal anti-inflammatory drug enteropathy
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ARTICLE
Role of proteinase‑activated receptors 1 and 2 in nonsteroidal anti‑inflammatory drug enteropathy Matteo Fornai1 · Rocchina Colucci2 · Carolina Pellegrini3 · Laura Benvenuti1 · Gianfranco Natale4 · Larisa Ryskalin4 · Corrado Blandizzi1 · Luca Antonioli1 Received: 23 January 2020 / Revised: 16 June 2020 / Accepted: 17 June 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Background The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can promote lower gastrointestinal detrimental effects. Proteinase-activated receptors 1 (PAR1) and PAR2 are involved in the pathophysiology of several digestive disorders. This study examines the contribution of PAR1 and PAR2 in NSAID-induced small intestinal injury, and to investigate the underlying mechanisms. Methods Male Wistar rats (40 weeks old) were treated with indomethacin (1.5 mg/kg BID) for 14 days. Subgroups of animals were treated intraperitoneally with TFFLR-NH2 (PAR1 agonist), AC55541 (PAR2 agonist), SCH79797 (PAR1 antagonist) or ENMD-1068 (PAR2 antagonist). After treatments, blood and feces were collected for the assessment of hemoglobin and calprotectin, respectively. The ileum was processed for the evaluation of myeloperoxidase (MPO), malondialdehyde (MDA), and the protein expression of occludin and activated caspase-3. Results Indomethacin elicited a significant intestinal damage, associated with a decrease in blood hemoglobin and an increase in tissue MPO, MDA and fecal calprotectin. In this setting, either the PAR1 agonist or PAR2 antagonist counteracted these changes, with the exception of MDA, which was unaffected. By contrast, the PAR1 antagonist or PAR2 agonist did not exert any effect on all the parameters. Indomethacin also decreased occludin and increased activated caspase-3 expression in ileal tissues. The PAR1 agonist or PAR2 antagonist prevented the reduced occludin expression, while the PAR2 antagonist also decreased the levels of activated caspase-3. Conclusions PAR2 is involved in the pathogenesis of indomethacin enteropathy, through pro-inflammatory mechanisms and an impairment of the intestinal epithelial barrier. PAR1 activation and PAR2 inhibition could represent suitable strategies for the prevention of NSAID enteropathy. Keywords Nonsteroidal anti-inflammatory drugs (NSAIDs) · Enteropathy · Proteinase-activated receptors (PAR) · Fecal calprotectin · Intestinal epithelial barrier · Intestinal inflammation
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43440-020-00119-w) contains supplementary material, which is available to authorized users. * Matteo Fornai [email protected] 1
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
2
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35100 Padova, Italy
3
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
4
Department of Translational Research and New Technologies in Medicine and S
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