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

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.