Lipid-derived mediators in endogenous anti-inflammation and resolution: lipoxins
and aspirin-triggered 15-epi-lipoxins
#MMPMID12806051
Serhan CN
; Chiang N
ScientificWorldJournal
2002[Jan]; 2
(?): 169-204
PMID12806051
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It is well appreciated that lipid-derived mediators play key roles in
inflammation and many other physiologic responses where multicellular processes
are involved. Among them, lipoxins (LX) and aspirin-triggered LX (ATL) evoke
actions of interest in a range of physiologic and pathophysiologic processes, and
these two series have emerged as founding members of the first class of
lipid/chemical mediators "switched on" in the resolution phase of an inflammatory
reaction. These unique compounds possess a trihydroxytetraene structure and are
both structurally and functionally distinct among the many groups of
lipid-derived bioactive mediators. LXA4 and 15-epi-LXA4 (a member of the ATL
series) display leukocyte-selective actions that enable them to serve as
endogenous "stop signals" in multicellular events in that they modulate
adherence, transmigration, and chemotaxis. Both LXA4 and 15-epi-LXA elicit these
responses via a G protein-coupled receptor (GPCR), termed ALXR, identified in
human and murine tissues. Among eicosanoids, ALXR is stereoselective for LXA4
(5S,6R,15S-trihydroxy-7,9,13- trans-11-cis-eicosatetraenoic acid). Its
aspirin-triggered 15 R epimer (15-epi-LXA4) and their bioactive stable analogs
act in the subnanomolar to nanomolar range in human cellular systems and murine
models of acute inflammation and reperfusion. ALXR also has the ability to
interact with a wide panel of small peptides that give different signaling
responses in vitro than LXA4 or its analogs, suggesting that ALXR is capable of
serving as a multirecognition receptor in immune responses. Characterization of
ALXR and development of metabolically stable LX and ATL analogs that are mimetics
rapidly advanced our appreciation of the mechanism of LX actions and the
potential utility of these counter-regulatory biocircuits in the quest to control
local inflammatory events. In this on-line update, LX and ATL biosynthesis and
the LXA4 specific receptor, termed ALXR, are reviewed with a focus on their roles
in inflammation and resolution with respect to pharmacology, molecular biology,
and signal transduction in several cell types and animal models investigated thus
far.
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