Background Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic neuroinflammation, known as part of pathology in Alzheimer’s disease (AD) brain. Methods Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in post mortem hippocampal tissue from AD-patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). Results Presence of SPMs and SPM receptors was demonstrated in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD - both in CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated to mini-mental state examination (MMSE) scores. Conclusions The resolution pathway exists in the brain and described alterations strongly suggest its dysfunction in AD. Correlations with MMSE suggest a connection with cognitive function in AD.

Recent evidence suggests that specialized lipid mediators derived from polyunsaturated fatty acids control resolution of inflammation, but little is known about resolution pathways in vascular injury. We sought to determine the actions of D-series resolvin (RvD) on vascular smooth muscle cell (VSMC) phenotype and vascular injury. Human VSMCs were treated with RvD1 and RvD2, and phenotype was assessed by proliferation, migration, monocyte adhesion, superoxide production, and gene expression assays. A rabbit model of arterial angioplasty with local delivery of RvD2 (10 nM vs. vehicle control) was employed to examine effects on vascular injury in vivo. Local generation of proresolving lipid mediators (LC-MS/MS) and expression of RvD receptors in the vessel wall were assessed. RvD1 and RvD2 produced dose-dependent inhibition of VSMC proliferation, migration, monocyte adhesion, superoxide production, and proinflammatory gene expression (IC50≈0.1-1 nM). In balloon-injured rabbit arteries, cell proliferation (51%) and leukocyte recruitment (41%) were reduced at 3 d, and neointimal hyperplasia was attenuated (29%) at 28 d by RvD2. We demonstrate endogenous biosynthesis of proresolving lipid mediators and expression of receptors for RvD1 in the artery wall. RvDs broadly reduce VSMC responses and modulate vascular injury, suggesting that local activation of resolution mechanisms expedites vascular homeostasis.

KM, Gronert K, Puder M. Intravenous fish oil lipid emulsion promotes a shift toward anti-inflammatory proresolving lipid mediators.

Currently, all three cytochrome P450 1 (CYP1) monooxygenases are believed to participate in lipid mediator biosynthesis and/or their local inactivation; however, distinct metabolic steps are current unknown. We used multiple-reaction monitoring and LC-UV-MS/MS-based lipid-mediator metabololipidomics to identify and quantify three different lipid-mediator metabolomes in basal peritoneal and zymosan-stimulated inflammatory exudates, comparing Cyp1a1/1a2/1b1(–/–) C57BL/6J-background triple-knockout with C57BL/6J wild-type mice. Significant differences between untreated triple-knockout and wild-type mice were not found for peritoneal cell number or type, or basal CYP1 activities involving 11 identified metabolic steps. Following zymosan-initiated inflammation, 18 lipid mediators were identified including members of the eicosanoids and specialized pro-resolving mediators, i.e. resolvins and protectins. Compared with wild-type mice, Cyp1 triple-knockout mice exhibited increased neutrophil recruitment in zymosan-treated peritoneal exudates. Zymosan stimulation was associated with 8 statistically significantly altered metabolic steps: increased arachidonic acid-derived leukotriene B4 (LTB4) and decreased 5S-hydroxyeicosatetraenoic acid (5S-HETE); decreased docosahexaenoic acid-derived neuroprotectin D1/protectin D1 (NPD1/PD1), 17S-hydroxydocosahexaenoic acid (17S-HDHA), and 14S-HDHA; and decreased eicosapentaenoic acid-derived 18R-hydroxyeicosapentaenoic acid (18R-HEPE), 15S-HEPE, and 12S-HEPE. In neutrophils analyzed ex vivo, elevated LTB4 levels were shown to parallel increased neutrophil numbers, and 20-hydroxy-LTB4 formation was found to be deficient in Cyp1 triple-knockout mice. Together, these results demonstrate novel contributions of CYP1 enzymes to the local metabolite profile of lipid mediators that regulate neutrophilic inflammation.

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