Receptors for pro-resolving mediators as a therapeutic tool for smooth muscle remodeling-associated disorders

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.