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.