Sun Yating, Liu Xiaohui, Wang Lianli, Li Laifu, Quan Xiaojing, Shi Haitao, Wang Ting, Mei Lin, Chen Yindi, Zhang Yue, Li Jingyao, Meng Ruiting, Wang Jinhai, Dai Fei
Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Bone and Joint Surgery, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Eur J Pharmacol. 2023 May 5;946:175650. doi: 10.1016/j.ejphar.2023.175650. Epub 2023 Mar 10.
Enteric glial cells (EGCs) play an important role in visceral hypersensitivity associated with irritable bowel syndrome (IBS). Losartan (Los) is known to reduce pain; however, its function in IBS is unclear. The present study aimed to investigate Los's therapeutic effect on visceral hypersensitivity in IBS rats. Thirty rats were randomly divided into control, acetic acid enema (AA), AA + Los low, medium and high dose groups in vivo. EGCs were treated with lipopolysaccharide (LPS) and Los in vitro. The molecular mechanisms were explored by assessing the expression of EGC activation markers, pain mediators, inflammatory factors and angiotensin-converting enzyme 1(ACE1)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis molecules in colon tissue and EGCs. The results showed that the rats in the AA group showed significantly higher visceral hypersensitivity than the control rats, which was alleviated by different doses of Los. The expression of GFAP, S100β, substance P (SP), calcitonin gene-related peptide (CGRP), transient receptor potential vanilloid 1 (TRPV1), tumor necrosis factor (TNF), interleukin-1β (IL-1β) and interleukin-6 (IL-6) was considerably increased in colonic tissues of AA group rats and LPS-treated EGCs compared with control rats and EGCs, and reduced by Los. In addition, Los reversed ACE1/Ang II/AT1 receptor axis upregulation in AA colon tissues and LPS-treated EGCs. These results show that Los inhibits ACE1/Ang II/AT1 receptor axis upregulation by suppressing EGC activation, resulting in reduced expression of pain mediators and inflammatory factors, thereby alleviating visceral hypersensitivity.
肠胶质细胞（EGCs）在与肠易激综合征（IBS）相关的内脏超敏反应中起重要作用。已知氯沙坦（Los）可减轻疼痛；然而，其在IBS中的作用尚不清楚。本研究旨在探讨氯沙坦对IBS大鼠内脏超敏反应的治疗作用。将30只大鼠随机分为对照组、乙酸灌肠（AA）组、AA + Los低、中、高剂量组进行体内实验。体外实验中，用脂多糖（LPS）和氯沙坦处理肠胶质细胞。通过评估结肠组织和肠胶质细胞中肠胶质细胞激活标志物、疼痛介质、炎症因子和血管紧张素转换酶1（ACE1）/血管紧张素II（Ang II）/血管紧张素II 1型（AT1）受体轴分子的表达来探索分子机制。结果显示，AA组大鼠的内脏超敏反应明显高于对照组大鼠，不同剂量的氯沙坦可使其减轻。与对照组大鼠和肠胶质细胞相比，AA组大鼠结肠组织和LPS处理的肠胶质细胞中胶质纤维酸性蛋白（GFAP）、S100β、P物质（SP）、降钙素基因相关肽（CGRP）、瞬时受体电位香草酸亚型1（TRPV1）、肿瘤坏死因子（TNF）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的表达显著增加，而氯沙坦可使其降低。此外，氯沙坦可逆转AA结肠组织和LPS处理的肠胶质细胞中ACE1/Ang II/AT1受体轴的上调。这些结果表明，氯沙坦通过抑制肠胶质细胞激活来抑制ACE1/Ang II/AT1受体轴的上调，导致疼痛介质和炎症因子的表达降低，从而减轻内脏超敏反应。
