Artone Serena, Ray Shuvra, Williams Joseph J, Akbulut Kenan, Cordero Paul, Gómez-Úriz Ana M, Friedman Hannah R, Saline Anna V, Hart Isabel M, Vadivelan Elakia, Parigi Tommaso L, Pietropaoli Davide, Latella Giovanni, Sanderson Jeremy D, De Salvo Carlo, Oben Jude A, Pizarro Theresa T, De Santis Stefania
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States.
Department of Life, Health & Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
J Crohns Colitis. 2025 Jun 4;19(6). doi: 10.1093/ecco-jcc/jjaf083.
The renin-angiotensin system (RAS) is known to modulate fibrosis, which is a common complication of ileal Crohn's disease. We tested the efficacy of losartan, an angiotensin receptor blocker, to treat intestinal fibrosis in relevant preclinical models of Crohn's-like disease.
Effector molecules of the RAS were mined in a large publicly available RNA-Seq dataset of intestinal biopsies from Crohn's patients and healthy individuals, and the presence of associated proteins was confirmed by immunohistochemistry in full-thickness intestinal tissues. Losartan's efficacy in altering mediators of the RAS and of fibrosis was tested in vitro using activated CCD-18Co fibroblasts, while its in vivo effects were investigated by administering losartan to SAMP1/YitFc (SAMP) mice, a well-described model of Crohn's-like disease that progressively develops both ileal-specific inflammation and fibrosis, using either therapeutic or maintenance of remission (treatment after dexamethasone) approaches.
Angiotensinogen, an upstream regulator of the RAS, and the downstream effector, angiotensin II receptor type 1, expressed on target cells, are both increased in involved vs non-involved gut mucosa from Crohn's patients compared to healthy controls. In vitro, losartan suppresses the expression of molecules related to fibrosis, fibroblast-to-myofibroblast differentiation, collagen deposition, and cytoskeletal alterations. In vivo, losartan decreases both inflammation and fibrosis in SAMP mice with established disease, and prevents the reoccurrence of fibrosis following a novel relapse protocol.
Losartan, and other drugs targeting the RAS, may serve as an effective treatment to successfully dampen intestinal fibrosis during active inflammation, as well as prevent its progression after corticosteroid-induced remission in Crohn's patients.
肾素-血管紧张素系统（RAS）已知可调节纤维化，而纤维化是回肠克罗恩病的常见并发症。我们在相关的克罗恩病样疾病临床前模型中测试了血管紧张素受体阻滞剂氯沙坦治疗肠道纤维化的疗效。
在一个来自克罗恩病患者和健康个体的肠道活检大型公开RNA测序数据集中挖掘RAS的效应分子，并通过全层肠组织免疫组化确认相关蛋白的存在。使用活化的CCD-18Co成纤维细胞在体外测试氯沙坦改变RAS和纤维化介质的功效，同时通过将氯沙坦给予SAMP1/YitFc（SAMP）小鼠来研究其体内效应，SAMP小鼠是一种描述详尽的克罗恩病样疾病模型，会逐渐发展出回肠特异性炎症和纤维化，采用治疗或缓解维持（地塞米松后治疗）方法。
与健康对照相比，克罗恩病患者受累肠黏膜与未受累肠黏膜相比，RAS的上游调节因子血管紧张素原和靶细胞上表达的下游效应因子1型血管紧张素II受体均增加。在体外，氯沙坦抑制与纤维化、成纤维细胞向肌成纤维细胞分化、胶原蛋白沉积和细胞骨架改变相关分子的表达。在体内，氯沙坦可减轻已患疾病的SAMP小鼠的炎症和纤维化，并防止新的复发方案后纤维化的再次出现。
氯沙坦以及其他靶向RAS的药物可能是一种有效的治疗方法，可在克罗恩病患者的活动性炎症期间成功减轻肠道纤维化，并防止皮质类固醇诱导缓解后纤维化的进展。
