Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus

Abstract

Complete resolution of an acute inflammatory response and its return to homeostasis are essential for healthy tissues. Here, we overview ongoing efforts to characterize cellular and molecular mechanisms that govern the resolution of self-limited inflammation. Systematic temporal analyses of evolving inflammatory exudates using mediator lipidomics-informatics, proteomics, and cellular trafficking with murine resolving exudates demonstrate novel endogenous pathways of local-acting mediators that share both anti-inflammatory and pro-resolving properties. In murine systems, resolving-exudate leukocytes switch their phenotype to actively generate new families of mediators from major omega-3 fatty acids EPA and DHA termed resolvins and protectins. Recent advances on their biosynthesis and actions are reviewed with a focus on the E-series resolvins (RvE1, RvE2), D series resolvins (RvD1, RvD2) and the protectins including neuroprotectin D1/protectin D1 (NPD1/PD1) as well as their aspirin-triggered epimeric forms. Members of each new family demonstrate potent stereo-specific actions, joining the lipoxins as endogenous local signals that govern resolution and endogenous anti-inflammation mechanisms. In addition to their origins and roles in resolution biology in the immune system, recent findings indicate that these new mediator families also display potent protective actions in lung, kidney, and eye as well as enhance microbial clearance. Thus, these endogenous agonists of resolution pathways constitute a novel genus of chemical mediators that possess pro-resolving, anti-inflammatory, and antifibrotic as well as host-directed antimicrobial actions. These may be useful in the design of new therapeutics and treatments for diseases with the underlying trait of uncontrolled inflammation and redox organ stress.

Figure 1

New families of PUFA-derived lipid mediators and their roles in the progression of acute Inflammation. (a) Specialized chemical mediators and signals appear to be programmed at the tissue level to actively participate in leukocyte responses (PMN, monocytes and macrophages) required for resolution. The chemical mediators are involved in the initiation of acute inflammation, such as PGs and LT. With time, a class switching occurs toward pro-resolving lipid mediators. These mediators include (1) ω-6 PUFA arachidonic acid (AA)-derived lipoxins (LXs) and aspirin-triggered LXs (ATL); (2) ω-3 PUFA eicosapentaenoic acid (EPA)-derived resolvin E-series (RvEs); (3) docosahexaenoic acid (DHA)-derived resolvin D-series (RvDs) and protectins (PDs). PDs are also termed neuroprotectins when generated in neural tissues. LXA₄, ATL, resolvins and protectins share anti-inflammatory and pro-resolving properties, yet have distinct actions within the resolution orchestra. (b) Structures of LXA₄, ATLa and their representative stable analogs (Bannenberg et al., 2004; Chiang et al., 2006). For detailed bioactions in disease models, see Table 1.

Figure 2

E-series resolvins. Aspirin impacts the formation of resolvin E1 (RvE1) by acetylating COX-2 in vascular endothelial cells that stereoselectively generate 18R-hydroperoxy-EPE (18R-H(p)EPE). 18R-HEPE is further converted via sequential actions of leukocyte 5-LOX, leading to formation of RvE1. The complete stereochemistry of RvE1 was recently established. Microbial P-450s can also contribute to RvE biosynthesis via converting eicosapentaenoic acid (EPA) to 18-HEPE (Arita et al., 2005b). Human recombinant 5-LOX also generates resolvin E2 (RvE2) from 18-HEPE. At least two separate GPCRs can specifically interact with RvE1: (1) ChemR23, on mononuclear cells and DCs, and (2) BLT1, on human PMN. Also, when expressed on epithelial cells ChemR23 and RvE1 stimulated CD-55-dependent clearance of PMN from the mucosal surface (Campbell et al., 2007).

Figure 3

D-series resolvins and protectins. (a) Resolvin Ds: formed from docosahexaenoic acid (DHA), the proposed biosynthetic pathways reconstructed in vitro involve the lipoxygenase (LOX) product 17S-H(p)DHA, which is rapidly transformed by the LOX activity in human polymorphonuclear leukocyte (PMN) into two epoxide intermediates. These two novel epoxide intermediates open to form bioactive products denoted 17S-resolvin D series (RvD1-4). Aspirin also impacts the formation of resolvin D series by catalytically switching COX-2 to a 17R-lipoxygenase-like mechanism that generates 17R-H(p)DHA, and subsequently 17R-resolvin D series (AT-RvDs). (b) Protectins: the initial enzymatic product 17S-H(p)DHA is converted to neuroprotectin D1/PD1. The complete stereochemistries of the bioactive mediators and related natural isomers are established (see text for further details).