Novel endogenous small molecules as the checkpoint controllers in inflammation and resolution: entrée for resoleomics

Endogenously-generated small chemical mediators or autacoids play key roles in controlling inflammation and its organized resolution. Among them, lipoxins are the trihydroxy-tetraene-containing eicosanoids that are generated primarily by tight cell-cell interactions by way of transcellular biosynthesis and serve as local endogenous anti-inflammatory mediators. These "stop signals" in inflammation and other related processes may be involved in switching the cellular response from additional PMN recruitment toward monocytes (in a nonphlogistic fashion) that could lead to resolution of the inflammatory response or promotion of repair and healing. ASA impinges on this homeostatic system and evokes the endogenous biosynthesis of the carbon 15 epimers of lipoxins, namely ATLs, that mimic the bioactions of native LX in several biologic systems and, thus, can modulate in part, the beneficial actions of ASA in humans. Moreover, the temporal and spatial components in LX formation and actions are important determinants of their impact during an acute inflammatory reaction. Generation of lipid (ie, ATL) versus protein (ie, ANXA1) mediators during the host inflammatory response display different time courses. The temporal difference suggests that ALX could regulate PMN by interacting with each class of ligands within specific phases of the inflammatory response. ALX is the first cloned lipoxygenase-derived eicosanoid receptor. The signaling pathways and bioactions of ALX are cell type-specific. In agreement with in vitro results, ALX agonists, namely LXA4 and 15-epi-LXA4 and their stable analogs, regulate PMN during acute inflammation. In addition, it seems that LXs also display organ-specific actions, in addition to host defense and immune roles in the eye, kidney, lung, and oral and gastrointestinal tract and within bone marrow progenitors, possibly involving stem cells. The development of these few synthetic stable analogs has provided valuable tools to evaluate the biologic roles, significance, and pharmacologic actions of ALX and provided novel therapies for inflammatory diseases. The relationship between LX generation and current NSAID therapies is more intertwined than currently appreciated. ASA inhibits COX-1 and converts COX-2 into an ASA-triggered lipid mediator-generating system that produces an array of novel endogenous local autacoids from dietary omega-3 PUFA. Some of the local autacoids display potent anti-inflammatory or antineutrophil recruitment activity as well as impinge on the role of these compounds in resolution, and, thus, are termed "resolvins." It is not surprising that investigators recently found a protective action for COX-2 in cardiovascular disease. Together with the lipoxins and 15-epi-lipoxins, the identification of the resolvins gives us new avenues of approach in considering therapies for inflammation, cardiovascular diseases and cancer.