Inosine monophosphate and aspirin-triggered 15-epi-lipoxin A4 act in concert to regulate neutrophil trafficking: additive actions of two new endogenous anti-inflammatory mediators.
Regulation of neutrophil (PMN) trafficking by soluble mediators is a critical component in the outcome of host defense, inflammation resolution, and neutrophil-mediated tissue injury. Elucidation of the endogenous mediators that protect tissues from excess leukocyte traffic and aberrant PMN activation that can lead to tissue damage and chronic inflammation is of considerable interest, especially the endogenous mechanisms of anti-inflammation. To this end, we recently uncovered two new classes of mediators: inosine monophosphate (IMP) and aspirin-triggered 15(R)-epimers of native lipoxin A(4). Here, we examined the combined actions of both classes of compounds in regulating key events in neutrophil trafficking. Neutrophil rolling in mouse microvessels was inhibited by both IMP or 5S,6R,15R-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA(4)) in a concentration-dependent fashion. When combined, IMP (300 nM) and 15-epi-LX (10 nM) demonstrated additive inhibition of neutrophil rolling in microvessels. IMP and 15-epi-LX also significantly inhibited tumor necrosis factor-alpha (TNF-alpha)-induced neutrophil accumulation into the mouse air pouch in a dose-dependent manner. Again, the combination of low dose IMP (10 microg) and LX analog (5 microg) gave additive inhibition of neutrophil accumulation in this model. These results demonstrate the inhibition of neutrophil trafficking in two separate models by two different classes of small endogenous molecules. The additive inhibition by IMP and aspirin-triggered LX may represent key pathways that protect and resolve inflammatory responses that could be harnessed for treatment.
Wada
K
K
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Qiu
F H
FH
Stahl
G L
GL
Serhan
C N
CN
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007291:Inosine Monophosphate / Q000494:pharmacology*; D044045:Lipoxins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; C040527:lipoxin A4; D007291:Inosine Monophosphate; D001241:Aspirin