Gene Expression of Proresolving Lipid Mediator Pathways Is Associated With Clinical Outcomes in Trauma Patients.
OBJECTIVE
Specialized proresolving lipid mediators have emerged as powerful modulators of inflammation and activators of resolution. Animal models show significant benefits of specialized proresolving lipid mediators on survival and wound healing after major burn trauma. To date, no studies have investigated specialized proresolving lipid mediators and their relation to other lipid mediator pathways in humans after trauma. Here we determine if patients with poor outcomes after trauma have dysregulated lipid mediator pathways.


METHODS
We studied blood leukocyte expression of 18 genes critical to the synthesis, signaling, and metabolism of specialized proresolving lipid mediators and proinflammatory lipid mediators, and we correlated these expression patterns with clinical outcomes in trauma patients from the Inflammation and the Host Response to Injury study.


METHODS
Seven U.S. medical trauma centers.


METHODS
Ninety-six patients enrolled in the Inflammation and Host Response to Injury study, after blunt trauma and unambiguously classified as having uncomplicated or complicated recoveries. Twenty-eight healthy volunteers were enrolled as controls.


METHODS
None.


RESULTS
Within each patient, the 18 genes of interest were used to calculate scores for distinct families of lipid mediators, including resolvins, lipoxins, prostaglandins, and leukotrienes, as well as leukotriene to resolvin score ratios. Scores were built using a simple weighting scheme, taking into consideration both dependent and independent activities of enzymes and receptors responsible for lipid mediator biosynthesis and function. Individually, ALOX12, PTGS2, PTGES, PTGDS, ALOX5AP, LTA4H, FPR2, PTGER2, LTB4R, HPGD, PTGR1, and CYP4F3 were expressed differentially over 28 days posttrauma between patients with uncomplicated and complicated recoveries (p < 0.05). When all genes were combined into scores, patients with uncomplicated recoveries had differential and higher resolvin scores (p < 0.001) and lower leukotriene scores (p < 0.001). A final combined ratio was calculated for each patient, and posttrauma leukotriene score to resolvin score ratios were significantly lower in patients with uncomplicated clinical courses (p < 0.001).


CONCLUSIONS
proresolving lipid mediator lipidomics and/or protein expression, and identifying associated therapeutic targets, may influence the clinical management of trauma patients.
1Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. 2Trauma, Emergency Surgery, and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 3Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 4The Center for Surgery, Innovation, and Bioengineering, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Sarah K
SK
Orr
Kathryn L
KL
Butler
Douglas
D
Hayden
Ronald G
RG
Tompkins
Charles N
CN
Serhan
Daniel
D
Irimia
D000328:Adult; D016638:Critical Illness; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives; D005260:Female; D015870:Gene Expression / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D007362:Intensive Care Units; D007902:Length of Stay; D007962:Leukocytes / Q000276:immunology*; D015289:Leukotrienes / Q000235:genetics; D050356:Lipid Metabolism / Q000276:immunology*; D044045:Lipoxins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011453:Prostaglandins / Q000235:genetics; D014947:Wounds and Injuries / Q000276:immunology* / Q000401:mortality
D018836:Inflammation Mediators; D015289:Leukotrienes; D044045:Lipoxins; D011453:Prostaglandins; D015118:Eicosapentaenoic Acid