Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Potent Immunoresolvents

Abstract

Summary Resolvins are a new family of n-3 lipid mediators initially identified in resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited resolving exudates revealed that resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g. blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia

“…7,12,28,29 The 17R epimer or AT form can be generated endogenously by aspirin-acetylated cyclooxygenase-2 performing the initial conversion of DHA; however, aspirin-independent biosynthesis of ATRvD3 also occurs in mammalian tissues. 7,12,28 Recent work established a method for total organic synthesis of RvD3 and AT-RvD3 that enabled elucidation of the stereochemistry of these mediators. 12,29 In addition to peritonitis, 12 RvD3 biosynthesis also occurs after kidney ischemia and colitis.…”

“…7,12,28 Recent work established a method for total organic synthesis of RvD3 and AT-RvD3 that enabled elucidation of the stereochemistry of these mediators. 12,29 In addition to peritonitis, 12 RvD3 biosynthesis also occurs after kidney ischemia and colitis. 30,31 Of interest, intervention with nanoparticles designed to deliver AT-RvD3 and AT-RvD1 is able to rescue age-related delays in the normal resolution process.…”

“…12,20 Lung histology revealed interstitial and alveolar edema and inflammation in the left lung of acidinjured animals that was maximal at 24 hours and slowly decreased at 48 and 72 hours ( …”

“…11 Recently, the biosynthetic routes and complete stereochemistry for resolvin D3 (RvD3) and its aspirin-triggered epimer AT-RvD3 were elucidated. 12 Interestingly, RvD3 is generated later than RvD1 and RvD2 in the course of peritonitis, suggesting unique proresolving roles for RvD3. 12 Herein, in a self-limited murine model of ARDS, we present evidence demonstrating AT-RvD3 0 s ability to promote resolution of tissue injury through multiple mechanisms, including reduction of edema through actions on sodium channel expression and lymphatic vasculature, limiting infiltration of proinflammatory leukocytes into the lung and NF-kB activation, and accelerating recovery of epithelial barrier integrity and function by promoting proliferation of epithelial cells.…”

Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

“…Four resolvin receptors have been identified: ALX (also known as N ‐formyl peptide receptor 2), G protein–coupled receptor 32 (GPR32) 9, 10, 11, chemokine‐like receptor 1 (ChemR23) 12, and leukotriene B 4 receptor (BLT‐1) 13. Resolvin D1 (RvD1) binds to and activates both ALX and GPR32 in human tissue, while in murine tissue the actions of RvD1 are mediated by ALX 14.…”