Vascular injury induces a potent inflammatory response that influences vessel remodeling and patency, limiting long-term benefits of cardiovascular interventions such as angioplasty. Specialized proresolving lipid mediators (SPMs) derived from v-3 polyunsaturated fatty acids [eicosapentaenoic acid and docosahexaenoic acid (DHA)] orchestrate resolution in diverse settings of acute inflammation. We hypothesized that systemic administration of DHA-derived SPMs [resolvin D2 (RvD2) and maresin 1 (MaR1)] would influence vessel remodeling in a mouse model of arterial neointima formation (carotid ligation). In vitro, SPM treatment inhibited mouse aortic smooth muscle cell migration (IC 50 @ 1 nM) to a PDGF gradient and reduced TNF-a-stimulated p65 translocation, superoxide production, and proinflammatory gene expression (MCP-1). In vivo, adult FVB mice underwent unilateral carotid artery ligation with administration of RvD2, MaR1, or vehicle (100 ng by intraperitoneal injection at 0, 1, 3, 5, and 7 d after ligation). In ligated carotid arteries at 4 d, SPM treatment was associated with reduced cell proliferation and neutrophil and macrophage recruitment and increased polarization of M2 macrophages in the arterial wall. Neointimal hyperplasia (at 14 d) was notably attenuated in RvD2 (62%)-and MaR1 (67%)-treated mice, respectively. Modulation of resolution pathways may offer new opportunities to regulate the vascular injury response and promote vascular homeostasis.-Akagi, D., Chen, M., Toy, R., Chatterjee, A., Conte, M. S. Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice. FASEB J. 29, 2504-2513 (2015). www.fasebj.org

ObjectiveInflammation and its resolution are central to vascular injury and repair. Maresins comprise a new family of bioactive lipid mediators synthesized from docosahexaenoic acid, an ω-3 polyunsaturated fatty acid. They have been found to exert anti-inflammatory and pro-resolving responses in macrophages, neutrophils and bronchial epithelial cells and impart beneficial actions in murine models of peritonitis and colitis. We investigated the impact of maresin-1 (MaR1) on tumor necrosis factor alpha (TNF-α) induced inflammatory responses in human vascular endothelial (EC) and smooth muscle cells (VSMC).MethodsPrimary cultures of human saphenous vein EC and VSMC were employed. We tested the naturally occurring MaR1 as modulator of TNF-α effects, with examination of monocyte adhesion, oxidant stress, and intracellular inflammatory signaling pathways.ResultsMaR1 attenuated TNF-α induced monocyte adhesion and reactive oxygen species (ROS) generation in both EC and VSMC, associated with down-regulated expression (cell surface) of the adhesion molecule E-selectin (in EC) and NADPH-oxidases (NOX4, NOX1, NOX2). MaR1 attenuated TNF-α induced release of pro-inflammatory mediators by EC and VSMC. MaR1 caused an attenuation of TNF-α induced NF-κB activation in both cell types associated with inhibition of I-κ Kinase (IKK) phosphorylation, IκB-α degradation and nuclear translocation of the NF- κB p65 subunit. MaR1 also caused a time-dependent increase in intracellular cyclic AMP (cAMP) in both naive and TNF-α stimulated VSMC and EC.ConclusionsMaR1 has broad anti-inflammatory actions on EC and VSMC, which may be partly mediated through up-regulation of cAMP and down-regulation of the transcription factor NF-κB. The results suggest that the pro-resolving lipid mediator MaR1 exerts homeostatic actions on vascular cells that counteract pro-inflammatory signals. These findings may have direct relevance for acute and chronic states of vascular inflammation.

The goal of this study was to compare outcomes among children treated nonoperatively vs operatively for completely displaced clavicle fractures. This was a retrospective cohort study of nonoperative vs operative treatment of completely displaced clavicle fractures sustained between 2006 and 2015 among pediatric patients. Data were collected on patient demographics, fracture characteristics, time to return to full activities, treatment complications, and patient-reported outcome measures. Fifty-five patients were identified in the nonoperative group, with a mean age of 11.6 years (range, 8–14 years). The operative group contained 55 patients, with a mean age of 14.3 years (range, 9–17 years). All fractures healed, with a mean time to return to full activities of 90.4 days in the nonoperative group and 89.7 days in the operative group ( P =.941). Twelve (22%) nonoperative patients sustained a refracture of their clavicle compared with 4 patients in the operative group ( P =.031). Fifteen patients (27%) in the operative group required a second surgery for removal of surgical implants. On the shortened form of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) survey, 17 of the 22 nonoperative patients reported a score of zero (indicating no disability) (range, 0–7) vs 22 of 25 in the operative group (range, 0–9) ( P =.329). Patients treated nonoperatively had a 22% rate of refracture, whereas patients treated operatively had a 27% rate of undergoing a second surgery for removal of surgical implants. These data can aid in the shared decision-making process with patients and families when deciding on treatment for displaced pediatric clavicle fractures. [ Orthopedics . 2022;45(6):373–377.]

Introduction Resolution of acute inflammation is regulated by endogenous lipid mediators derived from polyunsaturated fatty acids such as docosahexaenoic acid (DHA), however little is known about mechanisms of resolution in vascular injury. We investigated the effects of the DHA-derived mediator Mar1 on VSMC phenotype responses. Methods Primary human VSMCs were obtained from saphenous vein. VSMC were pretreated with Mar1 (10-100nM) then exposed to TNF-α (10ng/ml), and inflammatory responses assessed using a monocyte adhesion (U937) assay, expression of cell adhesion molecules and pro-inflammatory molecules (qPCR, western blot, ELISA), and production of superoxide (DHE). VSMC migration was measured in a transwell assay with PDGF-AB as the agonist, and cyotskeletal changes were assessed by actin-phalloidin staining. Results Mar-1 (100 nM) reduced U937 adhesion to TNF-stimulated VSMC, VCAM-1, and pro-inflammatory cytokine (IL-6, IL-8) expression. Superoxide production measured by DHE fluorescence was reduced by 57% (p=0.002) and Nox4 expression was markedly attenuated (43%, p=0.01). Mar-1 (0.01-100nM) induced rapid cytoskeletal changes with increased cell area, and reduced VSMC migration (76%, p=0.004) to PDGF-AB (50ng/ml; Figure). Conclusions Mar-1 attenuates TNF-α inflammatory activation of VSMC, with reduction in pro-inflammatory gene expression, oxidant stress, and monocyte adhesion. Mar-1 reduces actin polymerization and inhibits VSMC chemotaxis to PDGF. Pro-resolving mediators may represent a new class of endogenous vascular therapeutics.

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