Traditionally, surgical diseases including emergency and injury care have garnered less attention and support internationally when compared to other medical specialties. Over the past decade however, healthcare professionals have increasingly advocated for the need to address the global burden of non-communicable diseases. Surgical disease, including traumatic injury, is among the top causes of death and disability worldwide and the subsequent economic burden is substantial, falling disproportionately on low- and middle-income countries (LMICs). The future of global health in these regions depends on a redirection of attention to diseases managed within surgical, anesthesia and emergency specialties. Increasing awareness of these disparities, as well as increasing focus in the realms of policy and advocacy, is crucial. While the barriers to providing quality trauma and emergency care worldwide are not insurmountable, we must work together across disciplines and across boundaries in order to negotiate change and reduce the global burden of surgical disease.

Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis - conditions that are responsible for considerable morbidity and mortality. Surgical or catheter-based procedures performed on affected blood vessels induce acute-on-chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall remodeling and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and a return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, to improve tools for clinical measurement, and to better define the potential for "resolution therapeutics" in vascular patients.

Objective: Inflammation is a key driver of excessive neointimal hyperplasia within vein grafts. Recent work demonstrates that specialized proresolving lipid mediators biosynthesized from omega-3 polyunsaturated fatty acids, such as resolvin D1 (RvD1), actively orchestrate the process of inflammation resolution. We investigated the effects of local perivascular delivery of RvD1 in a rabbit vein graft model. Methods: Ipsilateral jugular veins were implanted as carotid interposition grafts through an anastomotic cuff technique in New Zealand white rabbits (3–4 kg; N = 80). RvD1 (1 μg) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel (Sigma-Aldrich, St. Louis, Mo) or a thin bilayered poly(lactic-co-glycolic acid) (PLGA) film. No treatment (bypass only) and vehicle-loaded Pluronic gels or PLGA films served as controls. Delivery of RvD1 to venous tissue was evaluated 3 days later by liquid chromatography-tandem mass spectrometry. Total leukocyte infiltration, macrophage infiltration, and cell proliferation were evaluated by immunohistochemistry. Elastin and trichrome staining was performed on grafts harvested at 28 days after bypass to evaluate neointimal hyperplasia and vein graft remodeling. Results: Perivascular treatments did not influence rates of graft thrombosis (23%), major wound complications (4%), or death (3%). Leukocyte (CD45) and macrophage (RAM11) infiltration was significantly reduced in the RvD1 treatment groups vs controls at 3 days (60%−72% reduction; P < .01). Cellular proliferation (Ki67 index) was also significantly lower in RvD1-treated vs control grafts at 3 days (40%−50% reduction; P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% vs bypass only (P < .001) and by 63% vs vehicle gel (P < .001). RvD1-loaded PLGA films reduced neointimal formation at 28 days by 50% vs bypass only (P < .001). RvD1 treatment was also associated with reduced collagen deposition in vein grafts at 28 days. Conclusions: Local perivascular delivery of RvD1 attenuates vein graft hyperplasia without associated toxicity in a rabbit carotid bypass model. This effect appears to be mediated by both reduced leukocyte recruitment and decreased cell proliferation within the graft. Perivascular PLGA films may also impart protection through biomechanical scaffolding in this venous arterialization model. Our studies provide further support for the potential therapeutic role of specialized proresolving lipid mediators such as D-series resolvins in modulating vascular injury and repair. (J Vasc Surg 2018;■:1–12.) Clinical Relevance: Autologous vein bypass grafts are the most durable means for revascularization in peripheral vascular disease; however, midterm and long-term outcomes are limited by vein graft hyperplasia with associated vein graft failure. Endogenous proresolving lipid mediators such as resolvin D1 have the potential to attenuate vein graft hyperplasia by accelerating repair. This study provides proof of co...

BACKGROUND Trauma and hypovolemic shock are associated with mitochondrial dysfunction and septic complications. We hypothesize that hypovolemic shock and resuscitation results in peripheral blood mononuclear cell (PBMC) mitochondrial dysfunction that is linked to immunosuppression. METHODS Using a decompensated shock model, Long-Evans rats were bled to a MAP of 40 mmHg until the blood pressure could no longer be maintained without fluid infusion. Shock was sustained by incremental infusion of Lactated Ringer’s solution (LR) until 40% of the shed volume had been returned (severe shock). Animals were resuscitated with 4X the shed volume in LR over 60 minutes (resuscitation). Control animals underwent line placement, but were not hemorrhaged. Animals were randomized to control (n=5), severe shock (n=5), or resuscitation (n=6) groups. At each time point, PBMC were isolated for mitochondrial function analysis using flow cytometry and high resolution respirometry. Immune function was evaluated by quantifying serum IL-6 and TNF-α after PBMC stimulation with lipopolysaccharide (LPS). The impact of plasma on mitochondrial function was evaluated by incubating PBMC’s harvested following severe shock with control plasma. PBMC’s from control animals were likewise mixed with plasma collected following resuscitation. Student’s t-test and Pearson correlations were performed (significance: p <0.05). RESULTS Following resuscitation, PBMCs demonstrated significant bioenergetic failure with a marked decrease in basal, maximal, and ATP-linked respiration. Mitochondrial membrane potential also decreased significantly by 50% following resuscitation. Serum IL6 increased, while LPS stimulated TNF-α production decreased dramatically following shock and resuscitation. Observed mitochondrial dysfunction correlated significantly with IL6 and TNF-α levels. PBMCs demonstrated significant mitochondrial recovery when incubated in control serum, whereas control PBMCs developed depressed function when incubated with serum collected following severe shock. CONCLUSION Mitochondrial dysfunction following hemorrhagic shock and resuscitation was associated with the inhibition of PBMC response to endotoxin that may lead to an immunosuppressed state.

INTRODUCTION Although mitochondrial dysfunction is thought to contribute to the development of post-traumatic organ failure, current techniques to assess mitochondrial function in tissues are invasive and clinically impractical. We hypothesized that mitochondrial function in peripheral blood mononuclear cells (PBMCs) would reflect cellular respiration in other organs during hemorrhagic shock and resuscitation (HS&R). METHODS Using a fixed pressure HS model, Long Evan’s rats were bled to a mean arterial pressure (MAP) of 40 mmHg. When blood pressure could no longer be sustained without intermittent fluid infusion (Decompensated HS), Lactated Ringer’s (LR) was incrementally infused to maintain the MAP at 40 mmHg until 40% of the shed blood volume was returned (Severe HS). Animals were then resuscitated with 4X total shed volume in LR over 60 minutes (Resuscitation). Control animals underwent the same surgical procedures, but were not hemorrhaged. Animals were randomized to Control (n=6), Decompensated HS (n=6), Severe HS (n=6) or Resuscitation (n=6) groups. Kidney, liver, and heart tissues as well as PBMC’s were harvested from animals in each group to measure mitochondrial oxygen consumption using high resolution respirometry. Flow cytometry was used to assess mitochondrial membrane potential (Ψm) in PBMCs. One-way ANOVA and Pearson correlations were performed. RESULTS Mitochondrial oxygen consumption decreased in all tissues, including PBMC’s, following Decompensated HS, Severe HS, and Resuscitation. However, the degree of impairment varied significantly across tissues during HS&R. Of the tissues investigated, PBMC mitochondrial oxygen consumption and Ψm provided the closest correlation to kidney mitochondrial function during HS (complex I: r =0.65; complex II: r=0.65; complex IV: r=0.52; p<0.05). This association, however, disappeared with resuscitation. A weaker association between PBMC and heart mitochondrial function was observed but no association was noted between PBMC and liver mitochondrial function. CONCLUSION All tissues including PBMC’s demonstrated significant mitochondrial dysfunction following HS&R. Although PBMC and kidney mitochondrial function correlated well during hemorrhagic shock, the variability in mitochondrial response across tissues over the spectrum of hemorrhagic shock and resuscitation limits the usefulness of using PBMC’s as a proxy for tissue-specific cellular respiration.