Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6905126, Israel; Adelson School of Medicine, Ariel University, Ariel 4077625, Israel.
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6905126, Israel.
Pharmacol Res. 2021 Feb;164:105340. doi: 10.1016/j.phrs.2020.105340. Epub 2020 Dec 1.
Respiratory airway, blood vessel and intestinal wall remodeling, in which smooth muscle remodeling plays a major role, is a key pathological event underlying the development of several associated diseases, including asthma, cardiovascular disorders (e.g., atherosclerosis, hypertension, and aneurism formation), and inflammatory bowel disease. However, the mechanisms underlying these remodeling processes remain poorly understood. We hypothesize that the creation of chronic inflammation-mediated networks that support and exacerbate the airway, as well as vascular and intestinal wall remodeling, is a crucial pathogenic mechanism governing the development of the associated diseases. The failed inflammation resolution might be one of the causal pathogenic mechanisms. Hence, it is reasonable to assume that applying specialized, pro-resolving mediators (SPMs), acting via cognate G-protein coupled receptors (GPCRs), could potentially be an effective pathway for treating these disorders. However, several obstacles, such as poor understanding of the SPM/receptor signaling pathways, SMP rapid inactivation as well as their complex and costly synthesis, limit their translational potential. In this connection, stable, small-molecule SPM mimetics and receptor agonists have emerged as new, potentially suitable drugs. It has been recently shown in preclinical studies that they can effectively attenuate the manifestations of asthma, atherosclerosis and Crohn's disease. Remarkably, some biased SPM receptor agonists, which cause a signaling response in the desired inflammation pro-resolving direction, revealed similar beneficial effects. These encouraging observations suggest that SPM mimetics and receptor agonists can be applied as a novel approach for the treatment of various chronic inflammation conditions, including airway, vascular and intestinal wall remodeling-associated disorders.
呼吸道、血管和肠壁重塑，其中平滑肌重塑起着主要作用，是几种相关疾病（如哮喘、心血管疾病（如动脉粥样硬化、高血压和动脉瘤形成）和炎症性肠病）发展的关键病理事件。然而，这些重塑过程的机制仍知之甚少。我们假设，慢性炎症介导的网络的创建，这些网络支持并加剧气道以及血管和肠壁重塑，是控制相关疾病发展的关键致病机制。炎症消退失败可能是其中一个因果致病机制。因此，可以合理地假设，应用专门的、促进解决的介质（SPM），通过同源 G 蛋白偶联受体（GPCR）发挥作用，可能是治疗这些疾病的有效途径。然而，一些障碍，如对 SPM/受体信号通路的理解不足、SPM 的快速失活以及它们复杂且昂贵的合成，限制了它们的转化潜力。在这方面，稳定的小分子 SPM 模拟物和受体激动剂已经成为新的、潜在合适的药物。最近的临床前研究表明，它们可以有效减轻哮喘、动脉粥样硬化和克罗恩病的症状。值得注意的是，一些偏向性的 SPM 受体激动剂，它们在所需的炎症解决方向引起信号反应，也显示出类似的有益效果。这些令人鼓舞的观察结果表明，SPM 模拟物和受体激动剂可以作为治疗各种慢性炎症疾病的新方法，包括与气道、血管和肠壁重塑相关的疾病。
