Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

Abstract

Specialized pro-resolving mediators (SPMs) are enzymatically derived from essential fatty acids and have important roles in orchestrating the resolution of tissue inflammation -that is, catabasis. Host responses to tissue infection elicit acute inflammation in an attempt to control invading pathogens. SPMs are lipid mediators that are part of a larger family of pro-resolving molecules, which includes proteins and gases, that together restrain inflammation and resolve the infection. These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defence. Here, we focus primarily on SPMs and their roles in lung infection and inflammation to illustrate the potent actions these mediators play in restoring tissue homeostasis after an infection.Acute inflammation is a vital response to infection that is initiated within seconds of pathogen detection 1 . Granulocytes are rapidly recruited to sites of infection 2 , where they become activated and augment the resident capacity of infected tissue to kill and ultimately clear the pathogen 3 . These early events in the host response to infection are essential for survival and are coordinated by several families of pro-inflammatory mediators, including lipid mediators (such as prostaglandins and leukotrienes), cytokines and chemokines. These pro-inflammatory mediators have overlapping and distinct functions and ultimately induce an increase in vascular permeability and orchestrate leukocyte recruitment. This leads to the cardinal signs of tissue inflammation -namely calor, rubor, tumor, dolor and potentially functio laesa (FIG. 1).Recently, a new array of molecules that function in the resolution of inflammation were elucidated and named specialized pro-resolving mediators (SPMs) 4,5 . Many of these SPMs are produced during the acute inflammatory response 6 , and their structure, biosynthesis and organic synthesis have been recently reviewed (see REF. 5). Typically, acute inflammatory responses to pathogens are self-limiting, and there is a growing appreciation that SPMs have pivotal anti-inflammatory and anti-infective roles in tissue catabasis 4 . For effective Correspondence to B.D.L. blevy@partners.org. Competing interests statementThe authors declare competing interests: see Web version for details. DATABASES ClinicalTrials.gov: http://www.clinicaltrials.gov ALL LINKS ARE ACTIVE IN THE ONLINE PDF HHS Public AccessAuthor manuscript Nat Rev Immunol. Author manuscript; available in PMC 2017 January 18. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript resolution of inflammation to occur in tissues, cessation of granulocyte recruitment is required in conjunction with the recruitment and differentiation of macrophages, which help clear inflammatory cells and tissue debris to restore tissue homeostasis 7 . Granulocytes in the tissue undergo apoptosis during the resolution of inflammation to prevent bystander tissue injury occurring from the release of potentially toxic cellular conten...

Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators

“…3B). The 15-epi LXA 4 is the 15(R) epimer of LXA 4 , yet these epimers have distinct biosynthetic pathways (11). As a control, we also used the coculture system to assess transcellular generation of LXA 4 .…”

“…As increasing FEV 1 /FVC ratio remains a key therapeutic objective of clinical therapy, one strategy may be direct replacement of the absent proresolving lipid mediator. Multiple studies have demonstrated that exogenous administration of specialized proresolving mediators improves morbidity and mortality outcomes following infection (11). In particular, the administration of a LXA 4 analog in mice challenged intratracheally with P. aeruginosa led to reduced neutrophil infiltration, weight loss, and bacterial burden, resulting in overall lessening of disease severity (15).…”

“…proinflammatory cascades, recent studies have also identified immunomodulatory and proresolving functions (11,12). In particular, lipoxins decrease neutrophil extravasation and enhance macrophage efferocytosis, thus promoting the resolution of inflammation and a return to tissue homeostasis (13,14).…”

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50–Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

“…In addition to its well-known role as a pharmaceutical target for anti-inflammatory drugs in inflammatory diseases, COX-2 also exerts versatile biological activities to resolve inflammation (7)(8)(9). At the onset of inflammation, COX-2 has a potent proinflammatory effect, predominantly through the generation of PGE 2 , whereas in the resolution phase, COX-2 is responsible for producing proresolving PGs, such as PGD 2 , 15-deoxy-D 12,14 -PGJ 2 , and PGF 2a (10)(11)(12)(13).…”

Western lifestyle and immunopathology of multiple sclerosis

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