Institut de Recherche en Santé Digestive, Université de Toulouse, INSERM, INRA, ENVT, UPS, U1220, CHU Purpan, CS60039, Toulouse, France.
CVasThera, Arobase Castres-Mazamet, Castres, France.
Inflamm Bowel Dis. 2021 Nov 15;27(Suppl 2):S33-S37. doi: 10.1093/ibd/izab244.
A new paradigm has been added for the treatment of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. In addition to resolving symptoms and inflammatory cell activation, the objective of tissue repair and mucosal healing is also now considered a primary goal. In the search of mediators that would be responsible for delayed mucosal healing, protease-activated receptor-1 (PAR-1) has emerged as a most interesting target. Indeed, in Crohn's disease, the endogenous PAR-1 agonist thrombin is drastically activated. Activation of PAR-1 is known to be associated with epithelial dysfunctions that hamper mucosal homeostasis. This review gathers the scientific evidences of a potential role for PAR-1 in mucosal damage and mucosal dysfunctions associated with chronic intestinal inflammation. The potential clinical benefits of PAR-1 antagonism to promote mucosal repair in CD patients are discussed. Targeted local delivery of a PAR-1 antagonist molecule such as CVT120165, a formulated version of the FDA-approved PAR-1 antagonist vorapaxar, at the mucosa of Crohn's disease patients could be proposed as a new indication for IBD that could be rapidly tested in clinical trials.
一种新的范式已经被添加到治疗炎症性肠病（如克罗恩病和溃疡性结肠炎）中。除了缓解症状和炎症细胞激活外，组织修复和黏膜愈合也被认为是主要目标。在寻找负责延迟黏膜愈合的介质时，蛋白酶激活受体-1（PAR-1）已成为最有趣的靶标。事实上，在克罗恩病中，内源性 PAR-1 激动剂凝血酶被剧烈激活。PAR-1 的激活与阻碍黏膜稳态的上皮功能障碍有关。这篇综述收集了 PAR-1 在与慢性肠道炎症相关的黏膜损伤和黏膜功能障碍中的潜在作用的科学证据。讨论了 PAR-1 拮抗作用促进 CD 患者黏膜修复的潜在临床获益。在克罗恩病患者的黏膜局部给予 PAR-1 拮抗剂分子（如 CVT120165，一种经过 FDA 批准的 PAR-1 拮抗剂 vorapaxar 的配方）可能被提议作为一种新的 IBD 适应证，这可以在临床试验中快速进行测试。
