acute lung injury ( ali ) is a major cause of morbidity and mortality and exacts an enormous health care burden . current treatment is merely supportive , and the lack of pathophysiologically targeted strategies is conspicuous . neutrophil recruitment is a crucial component of ali , with the cxc chemokine receptor 2 ( cxcr2)/cxc ligand 1 ( cxcl1 ) axis being a critical determinant of that process in murine models of ali . rossaint and coworkers   have employed both genetic and pharmacological methods to show that reducing the generation of 12/15-lipoxygenase ( 12/15-lo ) metabolites of arachidonate can inhibit neutrophil recruitment by attenuating cxcr2 expression , with concomitant improvement in clinically meaningful parameters of edema formation and gas exchange . one important lesson from this study was the authors ' perseverance in the face of ' unexpected ' data . although mice lacking the 12/15-lo gene had reduced neutrophil recruitment , they surprisingly exhibited higher levels of cxcl1 in the serum and lung lavage fluid . a modest but apparently biologically significant decrease in surface expression of cxcr2 was identified in mice lacking 12/15-lo . this decrease in cxcr2 expression was associated with desensitization of receptor signaling to an extent sufficient to reduce the response of neutrophils to cxcl1 . data such as these have the potential to challenge conventional thinking about the magnitude of changes in receptor expression that may be biologically significant . a crucial role for 12/15-lo metabolite(s ) in regulating chemokine - dependent neutrophil trafficking may have substantial therapeutic implications in ali and other forms of acute inflammatory tissue injury . however , translating these findings first requires that the specific metabolite promoting chemokine action , its cognate receptor , or the enzyme responsible for its synthesis be definitively identified . first , the mouse genome contains one gene coding for the dual lipoxygenase 12/15-lo , while in the human there are two separate genes encoding each of these lipoxygenase enzymes . to complicate matters further , products of these two enzymes may have opposite actions , with 12-hete generally possessing pro - inflammatory properties , and 15-hete and lipoxins typically described as being anti - inflammatory . this same research group has previously reported that 12-hete regulates vascular permeability through a cxcr2 mechanism   and this product is therefore a potential candidate for the metabolite likewise responsible for enhancing neutrophil recruitment . studies by others in a model of atherosclerosis   or asthma   also suggested that 12/15-lo products have net pro - inflammatory properties . there are , however , examples where 12/15-lo products have net anti - inflammatory features . rossaint and colleagues also employed a pharmacological inhibitor of 12/15-lo , cinnamyl-3,4-dihydroxy - alpha - cyanocinnamate ( cdc ) , but this too is insufficient to clarify the lipid mediator(s ) responsible for promoting chemokine action owing to a lack of specificity . in fact , cdc has recently been reported to be a more potent inhibitor for 5-lo than for 12-lo in vitro in human neutrophils and in vivo in a rat model . a final factor contributing to uncertainty about the pertinent metabolite(s ) derived from 12/15-lo is our ignorance about , and thus our inability to antagonize or delete , their cognate receptors . although a receptor for 12-hete has recently been proposed , its functionality has not been tested in ali . together , these factors have resulted in a far less comprehensive understanding of 12/15-lo products and their therapeutic targeting than has been the case with other lipid mediators , most notably prostanoids and leukotrienes . the findings presented in this manuscript provide additional motivation for investigators to identify the products of 12/15-lo and their receptors that regulate neutrophil recruitment as a prelude to a possible breakthrough in ali research . leukotriene b4 ( ltb4 ) has long been known to regulate chemotactic activity of human neutrophils . moreover , interactions between ltb4 and the cxcl1/cxcr2 axis in regulating neutrophil recruitment have also been recognized . for example , cross - talk between 12/15-lo products or ltb4 with the monocyte chemoattractant mcp-1 ( ccl2 ) has been described . unfortunately , this rich literature on the interplay between chemokines / cytokines and lipid mediators is often ignored in reviews about neutrophil recruitment . the synthesis or actions of lipid mediators have proven far more amenable to therapeutic targeting than have those of chemokines . the work of rossaint and colleagues provides an impetus to identify the precise mediator derived from 12/15-lo so that it or its receptor can be targeted as a potential strategy to improve outcomes of ali . ali : acute lung injury ; cdc : cinnamyl-3,4-dihydroxy - alpha - cyanocinnamate ; lo : lipoxygenase ; ltb4 : leukotriene b4 .
new therapeutic approaches are sorely needed for acute lung injury . 
 neutrophil recruitment is a pathological hallmark of this syndrome , and is mainly regulated by cxc chemokine receptor 2 and its ligand cxc ligand 1 . 
 rossaint and colleagues have described a new mechanism for regulation of this axis by 12/15-lipoxygenase products . 
 this work opens the door for new therapeutic approaches and highlights the crucial interplay between lipid mediators and chemokines , a time - honored but often - ignored concept .