Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology

Abstract

Acute inflammation is a host-protective response that is mounted in response to tissue injury and infection. Initiated and perpetuated by exogenous and endogenous mediators, acute inflammation must be resolved for tissue repair to proceed and for homeostasis to be restored. Resolution of inflammation is an actively regulated process governed by an array of mediators as diverse as those that initiate inflammation. Among these, resolvins have emerged as a genus of evolutionarily conserved pro-resolving mediators that act on specific cellular receptors to regulate leukocyte trafficking and blunt production of inflammatory mediators, while promoting clearance of dead cells and tissue repair. Given that chronic unresolved inflammation is emerging as a central causative factor in the development of cardiovascular diseases, an understanding of the endogenous processes that govern normal resolution of acute inflammation is critical for determining why sterile maladaptive cardiovascular inflammation perpetuates. Here, we provide an overview of the process of resolution with a focus on the enzymatic biosynthesis and receptor-dependent actions of resolvins and related pro-resolving mediators in immunity, thrombosis and vascular biology. We discuss how nutritional and current therapeutic approaches modulate resolution and propose that harnessing resolution concepts could potentially lead to the development of new approaches for treating chronic cardiovascular inflammation in a manner that is not host-disruptive.

Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome

“…An increase in the gene expression of Alox5ap 24 hrs following FUS may contribute to the resolution of inflammation by affecting the activity of 5-lox and subsequently the production of lipoxins and resolvins39. Additionally, increased expression of Timp1 has been found to attenuate inflammation in endothelium;40 Lyz2 has been implicated in reduction of Il1β, Il6, Tnfα, and Ccl2 production in human ECs;41 Slamf7 has been shown to inhibit the production of proinflammatory cytokines42.…”

A cluster of immunoresolvents links coagulation to innate host defense in human blood

“…Hence, our results suggest a potential physiologic mechanism by which coagulation initiates the endogenous production of functional n-3-derived SPMs that affect innate immune cells. Because the physiologic coagulation of blood is protective in humans, SPM production by clots may be of direct relevance to pathophysiology events in surgery (41), infection (11, 27, 42, 43), vascular inflammation (44, 45), stroke, and cancer (46, 47). …”

Lipids in Parenteral Nutrition: Biological Aspects

“…The paradigm for an acute inflammatory response can now be viewed as consisting of 2 stages: initiation (productive and transition phases) and resolution . Traditionally, there has been a view that excess inflammatory mediator production underlies chronic inflammation, but, increasingly, evidence shows that disruptions in production of endogenous SPMs may be at least as equally important, as they not only actively terminate the production of inflammatory mediators but also directly stimulate macrophage phagocytosis of both apoptotic cells and bacteria, promote egress of phagocytes from sites of inflammation, regulate polymorphonuclear neutrophil (PMN) apoptosis, promote chemokine scavenging, and stimulate tissue repair and regeneration . Thus, SPMs have been shown to improve outcomes in many cell‐ and animal‐based models, limiting neutrophilic infiltration and enhancing macrophage resolution responses, and, consequently, may have an important role in conditions characterized by excessive, uncontrolled inflammation .…”

“…Thus, SPMs have been shown to improve outcomes in many cell‐ and animal‐based models, limiting neutrophilic infiltration and enhancing macrophage resolution responses, and, consequently, may have an important role in conditions characterized by excessive, uncontrolled inflammation . It is also important to note that some chronic inflammatory diseases are associated with defects in production of SPMs . Furthermore, administration of DHA or EPA increases resolvin production in animal models of inflammation, and human studies have shown that ω‐3 PUFA intake increases the concentration of resolvins and their biosynthetic pathway markers in plasma or serum .…”