New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration

Abstract

While protective, the acute inflammatory response when uncontrolled can lead to further tissue damage and chronic inflammation that is now widely recognized to play important roles in many commonly occurring diseases, such as cardiovascular disease, neurodegenerative diseases, metabolic syndrome, and many other diseases of significant public health concern. The ideal response to initial challenges of the host is complete resolution of the acute inflammatory response, which is now recognized to be a biosynthetically active process governed by specialized pro-resolving mediators (SPM). These chemically distinct families include lipoxins, resolvins, protectins and maresins that are biosynthesized from essential fatty acids. The biosynthesis and complete stereochemical assignments of the major SPM are established, and new profiling procedures have recently been introduced to document the activation of these pathways in vivo with isolated cells and in human tissues. The active resolution phase leads to tissue regeneration, where we've recently identified new molecules that communicate during resolution of inflammation to activate tissue regeneration in model organisms. This review presents an update on the documentation of the roles of SPMs and the biosynthesis and structural elucidation of novel mediators that stimulate tissue regeneration, coined conjugates in tissue regeneration. The identification and actions of the three families, maresin conjugates in tissue regeneration (MCTR), protectin conjugates in tissue regeneration (PCTR), and resolvin conjugates in tissue regeneration (RCTR), are reviewed here. The identification, structural elucidation and the pathways and biosynthesis of these new mediators in tissue regeneration demonstrate the host capacity to protect from collateral tissue damage, stimulate clearance of bacteria and debris, and promote tissue regeneration via endogenous pathways and molecules in the resolution metabolome.

Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

“…Unfortunately, side effects such as headaches, diarrhea, flushing and both muscle and joint pain can result in significant patient intolerability to the treatment (30,31). Other bioactive lipids, represented by the resolvin family, are proposed to modulate inflammation and adaptive repair mechanisms (32). These molecules have significant pharmacokinetic and development liabilities, including rapid metabolism, a consequent short half-life and a high cost of synthesis.…”

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…Indeed, there are several examples in the literature showing that a persistent neuroinflammatory response in the injured brain may result in neuronal and glial cell dysfunction, alterations in blood–brain barrier (BBB) homeostasis, or neuronal cell death. Inefficient anti‐inflammatory control by endogenous resolving mechanisms may play a pivotal role in igniting persisting neuroinflammation …”

Immunonutrition in Critical Illness: What Is the Role?

“…The SPMs function in the nanogram to picogram level and appear to act via multiple mechanisms including G‐protein receptor binding, and altering and driving a change in macrophage class from a proinflammatory M1 macrophage to a resolution M2 macrophage. The M2 macrophage is associated with resolution of inflammation and tissue regeneration . While there is still much research to be done on SPMs, we now know that ω‐3 FA are the precursors to these mediators which include resolvins, protectins, and maresins, all of which seem to minimize the inflammatory challenge and promote tissue regeneration .…”

“…For the future, we anticipate a critical role for these nutrient‐dependent mediators in treating disease and controlling excessive inflammation . Experts postulate that we may personalize our nutrition therapies in both an age‐dependent and gender‐dependent manner to improve health and reduce disease burden by enhancing local resolution of inflammation, both acute and chronic . For the present, SCCM/ASPEN Guidelines recommend the use of ω‐3 FA along with other immune‐modulating agents for adult patients in the SICU, but not the MICU, until alternative lipid emulsions (containing olive oil, medium‐chain triglycerides, and fish oil) are widely available and deemed beneficial to meaningful patient outcomes through rigorous trials in the United States…”