Inosine monophosphate and aspirin-triggered 15-epi-lipoxin A(4) 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 critic al component in the outcome of host defense, inflammation resolution, and n eutrophil-mediated tissue injury. Elucidation of the endogenous mediators t hat protect tissues from excess leukocyte traffic and aberrant PMN activati on that can lead to tissue damage and chronic inflammation is of considerab le interest, especially the endogenous mechanisms of anti-inflammation. To this end, we recently uncovered two new classes of mediators: inosine monop hosphate (IMP) and aspirin-triggered 15(R)-epimers of native lipoxin A(4). Here, we examined the combined actions of both classes of compounds in regu lating key events in neutrophil trafficking. Neutrophil rolling in mouse mi crovessels was inhibited by both IMP or 5S,6R,15R-trihydroxy-7,9,13-trans-1 1-cis-eicosatetraenoic acid (15-epi-LXA(4)) in a concentration- dependent f ashion. When combined, IMP (300 nM) and 15-epi-LX (10 nM) demonstrated addi tive inhibition of neutrophil rolling in microvessels. IMP and 15-epi-LX al so 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 mug) and LX analog (5 mug) gav e additive inhibition of neutrophil accumulation in this model. These resul ts demonstrate the inhibition of neutrophil trafficking in two separate mod els by two different classes of small endogenous molecules. The additive in hibition by IMP and aspirin-triggered LX may represent key pathways that pr otect and resolve inflammatory responses that could be harnessed for treatm ent.