Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35100, Padova, Italy.
Pharmacol Rep. 2020 Oct;72(5):1347-1357. doi: 10.1007/s43440-020-00119-w. Epub 2020 Jun 24.
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.
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.
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.
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.
非甾体抗炎药（NSAIDs）的使用会促进下消化道的不良影响。蛋白酶激活受体 1（PAR1）和 PAR2 参与了几种消化疾病的病理生理过程。本研究旨在研究 PAR1 和 PAR2 在 NSAID 诱导的小肠损伤中的作用，并探讨其潜在机制。
雄性 Wistar 大鼠（40 周龄）用吲哚美辛（1.5mg/kg BID）处理 14 天。部分动物经腹腔内给予 TFFLR-NH2（PAR1 激动剂）、AC55541（PAR2 激动剂）、SCH79797（PAR1 拮抗剂）或 ENMD-1068（PAR2 拮抗剂）。治疗后，采集血液和粪便分别用于血红蛋白和钙卫蛋白的评估。处理后，对回肠进行髓过氧化物酶（MPO）、丙二醛（MDA）和紧密连接蛋白和活化 caspase-3 的蛋白表达的评估。
吲哚美辛引起明显的肠道损伤，伴有血红蛋白降低和组织 MPO、MDA 和粪便钙卫蛋白增加。在此背景下，PAR1 激动剂或 PAR2 拮抗剂均能逆转这些变化，除 MDA 外，其余均不受影响。相反，PAR1 拮抗剂或 PAR2 激动剂对所有参数均无影响。吲哚美辛还降低了回肠组织中 occludin 的表达，增加了活化 caspase-3 的表达。PAR1 激动剂或 PAR2 拮抗剂可预防 occludin 表达降低，而 PAR2 拮抗剂还可降低活化 caspase-3 的水平。
PAR2 通过促炎机制和损害肠道上皮屏障参与吲哚美辛肠病的发病机制。PAR1 激活和 PAR2 抑制可能是预防 NSAID 肠病的合适策略。
