Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation

Abstract

Because inflammation is appreciated as a unifying basis of many widely occurring diseases, the mechanisms involved in its natural resolution are of considerable interest. Using contained, self-limited inflammatory exudates and a systems approach, novel lipid-derived mediators and pathways were uncovered in the resolution of inflammatory exudates. These new families of local mediators control both the duration and magnitude of acute inflammation as well as the return of the site to homeostasis in the process of catabasis. This new genus of specialized proresolving mediators ( New Solution for Resolution of Acute InflammationSurgical interventions, tissue injury, and microbial invasion each evoke acute inflammation that is ideally protective for the host and should be "self-limited." Resolution of this inflammatory response was believed to be passive and defined earlier by histopathology. [1][2][3][4] It is now also widely accepted that uncontrolled inflammation is a unifying component in many diseases, 5 including vascular diseases, 6 neurological disorders, 7 and host defense.2,5 Because resolution was believed to be passive, our initial contributions 8 -10 and those of other groups worldwide provided new evidence indicating that resolution is a biosynthetically active process.11-16 When we considered the routes between acute inflammation, chronic, or resolved, as decision paths, the self-limited response appeared to hold a solution to what endogenous mechanisms control the magnitude and duration of the acute response, including the cardinal signs of inflammation (Figure 1). Specifically, the author and colleagues systematically identified a novel genus of specialized pro-resolving mediators (SPM) that include nonredundant, distinct, new families of molecules that are locally acting mediators, namely resolvins, protectins, Supported by National Institutes of Health grants DE019938, GM038765, and DK074448. The content is solely the responsibility of the author and does not necessarily reflect the official views of NIDCR, NIGMS, NIDDK, or the National Institutes of Health. Address reprint requests to Prof. Charles N.

Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B 4 synthesis by inhibiting a calcium-activated kinase pathway

“…An important process in inflammation resolution is the dampening of proinflammatory molecules in a manner that does not compromise host defense (2). Thus, it is essential to understand at a molecular-cellular level how this critical process is achieved.…”

“…Hence, uncovering mechanisms to suppress inflammation and enhance resolution is of immense interest (2)(3)(4)(5). Resolution is orchestrated in part by specialized proresolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins (2), and by protein and peptide mediators (6).…”

Resolvin D1 reduces deterioration of tight junction proteins by upregulating HO-1 in LPS-induced mice

“…DHA-derived resolvins act as a cytoprotective mechanism against oxidant injury 6,7 and the pro-resolving mediators, eg, lipoxin A4 and resolvins, can return the permeability/edema to normal. 8 Previous studies have showed that RvD1 displays potent anti-oxidative stress, 9 anti-inflammation, and pro-resolving actions that have been demonstrated in mouse models of ALI. [10][11][12] Though they have been observed that RvD1 can reduce pulmonary edema induced by lipopolysaccharide (LPS), the effects of RvD1 on TJ protein remain elusive.…”

Development and in vivo efficacy of targeted polymeric inflammation-resolving nanoparticles

“…Ideally, this response is self-limited and leads to clearance of pathogens, cellular debris, and inflammatory mediators (1,2). However, an excessive inflammatory response impairs resolution and leads to chronic inflammation and subsequent tissue damage (2)(3)(4). Increasing evidence suggests that excessive inflammation and impaired resolution play central roles in several prevalent diseases including cardiovascular, metabolic, and neurodegenerative diseases (5).…”