Specialized Lipid Mediators Research Articles

The Omega-6 Lipid pathway shift is associated with neutrophil influx and structural lung damage in early cysticfibrosis lung disease.

In cystic fibrosis (CF), an imbalanced lipid metabolism is associated with lung inflammation. Little is known about the role that specific lipid mediators (LMs) exert in CF lung inflammation, and whether their levels change during early disease progression. Therefore, we measured airway LM profiles of young CF patients, correlating these with disease-associated parameters. Levels of omega (ω)-3/6 PUFAs and their LM derivatives were determined in bronchoalveolar lavage fluid (BALF) of children with CF ages 1-5 using a targeted high-performance liquid chromatography-tandem mass spectrometry approach. Hierarchical clustering analysis was performed on relative LM levels. Individual relative LM levels were correlated with neutrophilic inflammation (BALF %Neu) and structural lung damage (PRAGMA-CF %Disease). Significant correlations were included in a backward multivariate linear regression model to identify the LMs that are best related to disease progression. A total of 65 BALF samples were analysed for ω-3/6 lipid content. LM profiles clustered into an arachidonic acid (AA)-enriched and a linoleic acid (LA)-enriched sample cluster. AA derivatives like 17-OH-DH-HETE, 5-HETE, 5,15-diHETE, 15-HETE, 15-KETE, LTB4 and 6-trans-LTB4 positively correlated with BALF %Neu and/or PRAGMA %Dis. Contrastingly, 9-HoTrE and the LA derivatives 9-HoDE, 9(10)-EpOME, 9(10)-DiHOME, 13-HoDE, 13-oxoODE and 12(13)-EpOME negatively correlated with BALF %Neu and/or PRAGMA %Dis. 6-trans-LTB4 was the strongest predictor for BALF %Neu. 5-HETE and 15-KETE contributed most to PRAGMA %Dis prediction. Our data provide more insight into the lung lipidome of infants with CF, and show that a shift from LA derivatives to AA derivatives in BALF associates with early CF lung disease progression.

Lipidomic Analysis of Microfat and Nanofat Reveals Different Lipid Mediator Compositions.

Microfat and nanofat are commonly used in various surgical procedures, from skin rejuvenation to scar correction, to contribute to tissue regeneration. Microfat contains mainly adipocytes and is well suited for tissue augmentation, and nanofat is rich in lipids, adipose-derived stem cells, microvascular fragments, and growth factors, making it attractive for aesthetic use. The authors have previously demonstrated that the mechanical processing of microfat into nanofat significantly changes its proteomic profile. Considering that mechanical fractionation leads to adipocyte disruption and lipid release, they aimed to analyze their lipidomic profiles for their regenerative properties. Microfat and nanofat samples were isolated from 14 healthy patients. Lipidomic profiling was performed by liquid chromatography tandem mass spectrometry. The resulting data were compared against the Human Metabolome and LIPID MAPS Structure Database. MetaboAnalyst was used to analyze metabolic pathways and lipids of interest. From 2388 mass-to-charge ratio features, metabolic pathway enrichment analysis of microfat and nanofat samples revealed 109 pathways that were significantly enriched. Microfat samples revealed higher-intensity levels of sphingosines, different eicosanoids, and fat-soluble vitamins. Increased levels of coumaric acids and prostacyclin were found in nanofat. This is the first study to analyze the lipidomic profiles of microfat and nanofat, providing evidence that mechanical emulsification of microfat into nanofat leads to changes in their lipid profiles. From 109 biological pathways, antiinflammatory, antifibrotic, and antimelanogenic lipid mediators were particularly enriched in nanofat samples when compared with microfat. Although further studies are necessary for a deeper understanding of the composition of these specific lipid mediators in nanofat samples, the authors propose that they might contribute to its regenerative effects on tissue. Profiling the unique lipid mediators in nanofat and microfat enhances our understanding of their different therapeutic effects and allows us to link these specific mediators to antiinflammatory, pro-regenerative, or healing properties. Ultimately, this insight can advance personalized therapeutic strategies, where a specific type of fat is selected based on its optimal therapeutic effect.

Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis.

Ferroptosis is a form of regulated cell death that is intricately linked to cellular metabolism. In the forefront of research on ferroptosis, the peroxidation of polyunsaturated fatty acids has emerged as a key driver of oxidative damage to cellular membranes leading to cell death. Here, we review the involvement of polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), lipid remodeling enzymes and lipid peroxidation in ferroptosis, highlighting studies revealing how using the multicellular model organism Caenorhabditis elegans contributes to the understanding of the roles of specific lipids and lipid mediators in ferroptosis.

Resolvin D1 modulates periodontal ligament fibroblast function.

The resolution of inflammation is an active process mediated by specialized lipid mediators called lipoxins and resolvins. Periodontal ligament fibroblasts (PDLFs) play a significant role in periodontal regeneration. The purpose of the current study was to determine the impact of resolvin D1 (RvD1) on human PDLF cell wound healing and proliferation, receptor expression (G-protein-coupled receptor 32 [GPR32] and formyl peptidereceptor2 [ALX/FPR2]), and cytokine expression and release. PDLFs were stimulated with interleukin-1β (IL-1β) (500pg/ml) with and without RvD1 (100nM). RvD1 receptor expression was determined by quantitative real-time polymerase chain reaction (qPCR), immunofluorescence microscopy, and fluorescence-activated cell sorting. Wound closure was measured by a scratch assay, and proliferation was determined by bromodeoxyuridine incorporation. Interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1, cyclooxygenase-2, matrix metalloproteinases-1, -2, and -3 (MMP-1, -2, and -3), tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and -2), prostaglandin E2, and osteoprotegerin (OPG) gene expression and production were measured using qPCR and Western blotting, multiplex immunoassay, and enzyme-linked immunosorbent assay. PDLF expressed GPR32 and ALX/FPR2. RvD1 reversed IL-1β-induced inhibition of wound healing and proliferation of PDLF. IL-1β also induced the production of proinflammatory cytokines and MMPs. This effect was reversed by RvD1. RvD1 reversed IL-1β-induced inhibition of TIMP-1, TIMP-2, and OPG. The data suggested that RvD1 has a pro-wound healing, proliferative, and anti-inflammatory impact on the PDLF that favors periodontal regeneration.

Abstract P3007: Exposure To Particulate Air Pollution Dysregulates Splenic Inflammation Resolution And Erythrocyte Processing

Chronic exposure to ambient particulate matter (PM) increases the risk of cardiovascular disease (CVD). One proposed mechanism linking PM exposure and CVD is the induction of low-grade systemic inflammation that underlies disease progression. However, whether exposure to fine PM (PM 2.5 ) directly affects the endogenous pathways that resolve the inflammatory response is not known. Resolution of inflammation is distinct from anti-inflammation in that rather than blunting the magnitude of the initial inflammatory response, it is the active promotion and acceleration of its decay. Defective or insufficient resolution is a hallmark of many chronic inflammatory diseases including atherosclerosis and diabetes. Therefore, the overall goal of this study was to elucidate how PM exposure impacts the resolution of inflammation and how this relates to the subtle, but extensive pathological changes brought about by PM exposure. We found that in mice exposed PM 2.5 for 30 days there was a significant decrease in the abundance of specialized lipid mediators that promote resolution (SPMs) in the spleen. The changes in spleen are particularly critical due to its central role in regulating immune response dynamics and as a filter to remove senescent and damaged erythrocytes. While SPMs are known to enhance macrophage erythrophagocytosis ex vivo , how decreased in vivo abundance affects splenic function remains unclear. Therefore, we performed RNA sequencing of PM 2.5 -exposed spleens and found that numerous pathways involved in both erythrophagocytosis and myelopoiesis were significantly upregulated, including those related to myeloid cell homeostasis and development, erythrocyte differentiation, iron ion homeostasis, and heme biosynthesis and metabolism. Additionally, we identified significant alterations in circulating red blood cells, including decreased expression of CD47, a prominent marker of self and “don’t eat me signal”, on the surface of circulating erythrocytes after exposure to PM 2.5 , as well as increased red cell distribution width. Together, these data suggest that PM exposure alters red blood cells and may stimulate enhanced erythrophagocytosis in the spleen, increasing red blood cell turnover.

Resolution of Inflammation after Skeletal Muscle Ischemia-Reperfusion Injury: A Focus on the Lipid Mediators Lipoxins, Resolvins, Protectins and Maresins.

Skeletal muscle ischemia reperfusion is very frequent in humans and results not only in muscle destruction but also in multi-organ failure and death via systemic effects related to inflammation and oxidative stress. In addition to overabundance of pro-inflammatory stimuli, excessive and uncontrolled inflammation can also result from defects in resolution signaling. Importantly, the resolution of inflammation is an active process also based on specific lipid mediators including lipoxins, resolvins and maresins that orchestrate the potential return to tissue homeostasis. Thus, lipid mediators have received growing attention since they dampen deleterious effects related to ischemia–reperfusion. For instance, the treatment of skeletal muscles with resolvins prior to ischemia decreases polymorphonuclear leukocyte (PMN) infiltration. Additionally, remote alterations in lungs or kidneys are reduced when enhancing lipid mediators’ functions. Accordingly, lipoxins prevented oxidative-stress-mediated tissue injuries, macrophage polarization was modified and in mice lacking DRV2 receptors, ischemia/reperfusion resulted in excessive leukocyte accumulation. In this review, we first aimed to describe the inflammatory response during ischemia and reperfusion in skeletal muscle and then discuss recent discoveries in resolution pathways. We focused on the role of specialized pro-resolving mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) and their potential therapeutic applications.

Inflammation and resolution signaling in cardiac repair and heart failure.

SummaryUnresolved inflammation is a key mediator of advanced heart failure. Especially, damage, pathogen, and lifestyle-associated molecular patterns are the major factors in initiating baseline inflammatory diseases, particularly in cardiac pathology. After a significant cardiac injury like a heart attack, splenic and circulating leukocytes begin a highly optimized sequence of immune cell recruitment (neutrophils and monocytes) to coordinate effective tissue repair. An injured cardiac tissue repair and homeostasis are dependent on clearance of cellular debris where the recruited leukocytes transition from a pro-inflammatory to a reparative program through resolution process. After a cardiac injury, macrophages play a decisive role in cardiac repair through the biosynthesis of endogenous lipid mediators that ensure a timely tissue repair while avoiding chronic inflammation and impaired cardiac repair. However, dysregulation of resolution of inflammation processes due to cardiometabolic defects (obesity, hypertension, and diabetes), aging, or co-medication(s) lead to impaired cardiac repair. Hence, the presented review demonstrates the fundamental role of leukocytes, in particular macrophages orchestrate the inflammation and resolution biology, focusing on the biosynthesis of specialized lipid mediators in cardiac repair and heart failure. This work was supported by research funds from National Institutes of Health (AT006704, HL132989, and HL144788) to G.V.H. The authors acknowledges the use of Servier Medical Art image bank and Biorender that is used to create schematic Figures 1–3.

Reduced Plasma Extracellular Vesicle CD5L Content in Patients With Acute-On-Chronic Liver Failure: Interplay With Specialized Pro-Resolving Lipid Mediators.

Acute-on chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated cirrhosis (AD). It is characterized by a systemic hyperinflammatory state, leading to multiple organ failure. Our objective was to analyze macrophage anti-inflammatory protein CD5L in plasma extracellular vesicles (EVs) and assess its as yet unknown relationship with lipid mediators in ACLF. With this aim, EVs were purified by size exclusion chromatography from the plasma of healthy subjects (HS) (n=6) and patients with compensated cirrhosis (CC) (n=6), AD (n=11) and ACLF (n=11), which were defined as positive for CD9, CD5L and CD63 and their size, number, morphology and lipid mediator content were characterized by NTA, EM, and LC-MS/MS, respectively. Additionally, plasma CD5L was quantified by ELISA in 10 HS, 20 CC and 149 AD patients (69 ACLF). Moreover, macrophage CD5L expression and the biosynthesis of specialized lipid mediators (SPMs) were characterized in vitro in primary cells. Our results indicate that circulating EVs were significantly suppressed in cirrhosis, regardless of severity, and showed considerable alterations in CD5L and lipid mediator content as the disease progressed. In AD, levels of EV CD5L correlated best with those of the SPM RvE1. Analysis of total plasma supported these data and showed that, in ACLF, low CD5L levels were associated with circulatory (p<0.001), brain (p<0.008) and respiratory (p<0.05) failure (Mann-Whitney test). Functional studies in macrophages indicated a positive feedback loop between CD5L and RvE1 biosynthesis. In summary, we have determined a significant alteration of circulating EV contents in ACLF, with a loss of anti-inflammatory and pro-resolving molecules involved in the control of acute inflammation in this condition.

17R/S-Benzo-RvD1, a synthetic resolvin D1 analogue, attenuates neointimal hyperplasia in a rat model of acute vascular injury.

Persistent inflammation following vascular injury drives neointimal hyperplasia (NIH). Specialized lipid mediators (SPM) mediate resolution which attenuates inflammation and downstream NIH. We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty. Human venous VSMC and endothelial cells (EC) were employed in migration, cell shape, toxicity, proliferation and p65 nuclear translocation assays. Murine RAW 264.7 cells were utilized to test the effect of pro-resolving compounds on phagocytic activity. A model of rat carotid angioplasty was used to evaluate the effects of 17R/S-benzo-RvD1 (benzo-RvD1) and 17R-RvD1 applied to the adventitia via 25% Pluronic gel. Immunostaining was utilized to examine Ki67 expression and leukocyte recruitment. Morphometric analysis was performed on arteries harvested 14 days after injury. Exposure to benzo-RvD1 attenuated PDGF- stimulated VSMC migration across a range of concentrations (0.1-100 nM), similar to that observed with 17R-RvD1. Pre-treatment with either Benzo-RvD1 or 17R-RvD1 (10, 100nM) attenuated PDGF-BB-induced VSMC cytoskeletal changes to nearly baseline dimensions. Benzo-RvD1 demonstrated modest anti-proliferative activity on VSMC and EC at various concentrations, without significant cytotoxicity. Benzo-RvD1 (10nM) inhibited p65 nuclear translocation in cytokine-stimulated EC by 21% (p<0.05), similar to 17R-RvD1. Consistent with pro-resolving activities of other SPM, both 17R-RvD1 and benzo-RvD1 increased the phagocytic activity of RAW 264.7 cells against S. Aureus and Zymosan particles. There were no significant differences in Ki-67 or CD45 staining observed on day 3 after angioplasty. Periadventitial treatment with benzo-RvD1 reduced carotid neointimal area at 14 days compared to control (0.08 mm2 v. 0.18 mm2; p<0.05), with similar efficacy to 17R-RvD1. 17R/S-benzo-RvD1 and 17R-RvD1 exhibit similar pro-resolving and anti-migratory activity in cell-based assays, and both compounds attenuated NIH following acute arterial injury in rats. Further studies of the mechanisms of resolution following vascular injury, and the translational potential of SPM analogues, are indicated.

Endocannabinoid System and Its Regulation by Polyunsaturated Fatty Acids and Full Spectrum Hemp Oils.

The endocannabinoid system (ECS) consists of endogenous cannabinoids, their receptors, and metabolic enzymes that play a critical homeostatic role in modulating polyunsaturated omega fatty acid (PUFA) signaling to maintain a balanced inflammatory and redox state. Whole food-based diets and dietary interventions linked to PUFAs of animal (fish, calamari, krill) or plant (hemp, flax, walnut, algae) origin, as well as full-spectrum hemp oils, are increasingly used to support the ECS tone, promote healthy metabolism, improve risk factors associated with cardiovascular disorders, encourage brain health and emotional well-being, and ameliorate inflammation. While hemp cannabinoids of THC and CBD groups show distinct but complementary actions through a variety of cannabinoid (CB1 and CB2), adenosine (A2A), and vanilloid (TRPV1) receptors, they also modulate PUFA metabolism within a wide variety of specialized lipid mediators that promote or resolve inflammation and oxidative stress. Clinical evidence reviewed in this study links PUFAs and cannabinoids to changes in ECS tone, immune function, metabolic and oxidative stress adaptation, and overall maintenance of a well-balanced systemic function of the body. Understanding how the body coordinates signals from the exogenous and endogenous ECS modulators is critical for discerning the underlying molecular mechanisms of the ECS tone in healthy and disease states. Nutritional and lifestyle interventions represent promising approaches to address chronic metabolic and inflammatory disorders that may overlap in the population at risk. Further investigation and validation of dietary interventions that modulate the ECS are required in order to devise clinically successful second-generation management strategies.

Salivary levels of last generation specific pro‐resolving lipid mediators (SPMs) (protectin and maresin) in patients with cardiovascular and periodontal disease: A case‐control study

Periodontal disease and cardiovascular disease (CVD), which are both deemed to be triggered by inflammation, are recognized as public health problems. Evidence of host modulation via pro-resolving lipid shown in previous studies supports a two-way relationship between periodontitis and CVD. Last generation endogenous specific pro-resolution lipid mediators (SPMs) such as protectins (PDs) and maresins (MaRs) may have potential effects on inflammatory pathogenesis via activation and resolution mechanisms. Currently, there are no data on SPM levels in patients with CVD and periodontal disease. We aimed to evaluate salivary levels of PD and MaR in patients with CVD and periodontal disease. At total of 181 individuals comprising of 79 healthy controls (C) and 102 patients with diagnosed CVD were included cross-sectionally. Unstimulated total salivary samples were obtained, and clinical periodontal parameters were determined. Salivary levels of PD and MaR were evaluated by ELISA. The periodontal status of the study population was classified as gingivitis (g) or periodontitis (p). Patients with CVD showed lower sociodemographic characteristics, increased clinical periodontal parameters (p<.05), decreased salivary PD (p<.001), and increased salivary MaR levels (p>.05). In the CVDg group, leukocyte, hemoglobin, hematocrit, and high-density lipoprotein values were higher (p<.05). The CVDp group had a higher neutrophil-to-lymphocyte ratio (p<.05). While the PD level was highest in the Cg group, MaR was highest in the CVDp group. The salivary levels of PD and MaR were independent of other confounders in CVD and periodontal disease (p>.05). PDs and MaRs may play effective roles in pathogenesis associated with worsening cardiometabolic and periodontal status. These SPMs could also be predictors for conversion from a healthy (systemically and periodontally) to diseased state (CVD and/or periodontitis). Elucidation of the role of SPMs in the relationship between periodontal disease and CVD will enable the development of new host modulation strategies in the prevention and treatment of both diseases, and may also constitute an important public health step by increasing the quality of life of patients with CVD and periodontal disease.

The Utility of Novel Fish-Skin Derived Acellular Dermal Matrix (Kerecis) as a Wound Dressing Material

Background: The newly-approved Kerecis is a piscine acellular dermal xenograft. This piscine acellular dermal matrix (ADM) has specific bioactive lipid mediators, omega-3 polyunsaturated fatty acids, and has a positive effect on the process of wound healing. This study aimed to explore the utility of this novel material by comparing healing rates, and suggest the proper timing for applying Kerecis.&lt;br/&gt;Methods: Patients who visited the hospital with acute or chronic deep dermal wounds from June 2019 to May 2020 were enrolled in the study. A total of 48 patients were assessed. All wounds in the experimental group (n=16) were treated only once with Kerecis and a non-adherent absorptive foam material (Therasorb) to cover the ADM. In the control group, daily conventional dressings were provided. All wounds sizes were measured with mass-market computer software in a method suggested by the authors for the first time.&lt;br/&gt;Results: The mean healing rate proved to be faster in the Kerecis group (P&lt;0.05) versus the control group, and no complications were observed. It was statistically proved that treating burn wounds with the ADM showed better healing rates than the conventional method (P&lt;0.05).&lt;br/&gt;Conclusion: This study establishes that managing wounds with the ADM is likely to heal wounds faster than traditional dressings. In addition, for burn wounds, a prolonged application (10 days vs. 5 days after the onset) showed a better wound healing rate (98.8%±2.5% vs. 67.0%±14.3%, respectively, P=0.029).

Treatment Strategy of Intimal Hyperplasia Based on Resolution of Inflammation: Promised Future of Specialized Lipid Mediators

Treatment Strategy of Intimal Hyperplasia Based on Resolution of Inflammation: Promised Future of Specialized Lipid Mediators

Effects of antiemetic doses of dexamethasone on plasma mediators of inflammation resolution and pain after surgery in women

BackgroundDexamethasone is commonly given as an antiemetic during surgical procedures. It has immunosuppressive effects and can affect key enzymes involved in the synthesis of specialised lipid mediators of inflammation resolution (SPM) that direct inflammation resolution and have anti-nociceptive actions. This study examined the effect of dexamethasone on plasma SPM, and the relationship between SPM and perceived pain in women undergoing surgery. MethodsPlasma SPM were measured in samples obtained from two double-blind controlled interventions. The first, included 51 women mean age 53 ± 1.5 years, undergoing breast surgery allocated to either intravenous saline, or dexamethasone (4 mg or 8 mg) after induction of anaesthesia. The second study included 31 women of mean age 44 ± 0.5 years undergoing laparoscopic gynecological surgery that were allocated to either saline, or dexamethasone (4 mg). SPM (18-HEPE, 17-HDHA, RvE2, RvD1 17R-RvD1 and RvD2) were measured in plasma collected prior to induction of anaesthesia and at 24 h, and 6 weeks post-surgery. Pain was assessed using a verbal analogue scale at discharge from the post-anaesthesia recovery unit. The data from each study was combined to examine the effect of dexamethasone on plasma SPM. The relationship between pain score and SPM was examined using ordinal logistic regression. ResultsThe SPM 18-HEPE, 17-HDHA, RvE2, RvD1 17R-RvD1 and RvD2 were detectable in all plasma samples. There was no significant difference in any SPM due to dexamethasone over the duration of the study. There was a fall in 17-HDHA between baseline and 24 h in both the dexamethasone and saline groups (P = 0.003) but no change in the downstream SPM (RvD1, 17R-RvD1 and RvD2) or 18-HEPE and RvE2. Pain score was negatively related to levels of RvE2 measured prior to induction of anaesthesia (rho = −0.2991, P = 0.006) and positively related to BMI (rho = 0.279, P = 0.011). In ordinal logistic regression the odds ratio for RvE2 was 0.931 (CI 0.880, 0.986; P = 0.014); after adjusting for the effect of BMI indicating that an increase in RvE2 of 1 pg/ml would result in a 6.9 % fall in pain score. Allocation to a dexamethasone group did not influence the pain score or the relationship between RvE2 and pain score. ConclusionDexamethasone administered as an anti-emetic does not affect plasma SPM levels. An elevated RvE2 level prior to surgery is predictive of a lower perceived pain score post-anaesthesia.

Overexpression of cyclooxygenase-2 in adipocytes reduces fat accumulation in inguinal white adipose tissue and hepatic steatosis in high-fat fed mice

Cyclooxygenases are known as important regulators of metabolism and immune processes via conversion of C20 fatty acids into various regulatory lipid mediators, and cyclooxygenase activity has been implicated in browning of white adipose tissues. We generated transgenic (TG) C57BL/6 mice expressing the Ptgs2 gene encoding cyclooxygenase-2 (COX-2) in mature adipocytes. TG mice fed a high-fat diet displayed marginally lower weight gain with less hepatic steatosis and a slight improvement in insulin sensitivity, but no difference in glucose tolerance. Compared to littermate wildtype mice, TG mice selectively reduced inguinal white adipose tissue (iWAT) mass and fat cell size, whereas the epididymal (eWAT) fat depot remained unchanged. The changes in iWAT were accompanied by increased levels of specific COX-derived lipid mediators and increased mRNA levels of interleukin-33, interleukin-4 and arginase-1, but not increased expression of uncoupling protein 1 or increased energy expenditure. Epididymal WAT (eWAT) in TG mice exhibited few changes except from increased infiltration with eosinophils. Our findings suggest a role for COX-2-derived lipid mediators from adipocytes in mediating type 2 immunity cues in subcutaneous WAT associated with decreased hepatic steatosis, but with no accompanying induction of browning and increased energy expenditure.

Antiemetic doses of dexamethasone and their effects on immune cell populations and plasma mediators of inflammation resolution in healthy volunteers

IntroductionThe synthetic glucocorticoid dexamethasone is a commonly administered antiemetic. It has immunosuppressive effects and may alter postoperative blood glucose concentrations. Dexamethasone can effect key enzymes involved in inflammation resolution that is an active process driven by specialised lipid mediators of inflammation resolution (SPM). The purpose of this study in healthy volunteers was to examine whether dexamethasone effects cell populations and synthesis of SPM that are critical for the resolution of inflammation. MethodsThirty-two healthy volunteers were randomly allocated to receive saline (Control) or dexamethasone 2 mg, 4 mg or 8 mg intravenously. Venous blood samples were collected at baseline before administration of treatment, and at 4 h, 24 h and one-week post-treatment. At each time point, measurements included blood glucose and macrophage migration inhibition factor (MMIF), full blood count including lymphocyte subsets, monocytes, neutrophils, eosinophils and basophils by flow cytometry, and plasma SPM using liquid chromatography tandem mass spectrometry. The effect of dexamethasone dose and time on all measures was analysed using linear mixed models. ResultsThere was a dose-dependent increase in neutrophil count after dexamethasone that persisted for 24 h. In contrast, there was a dose-dependent reduction in counts of monocytes, lymphocytes, basophils and eosinophils 4 h after dexamethasone, followed by a rebound increase in cell counts at 24 h. Seven days after administration of dexamethasone, all cell counts were similar to baseline levels. MMIF concentration, glucose and natural killer cell counts were not significantly affected by dexamethasone. There was a significant gender effect on plasma SPM such that levels of 17-HDHA, RvD1, 17R-RvD1 and RvE2 in females were on average 14%–50% lower than males. In a linear mixed model that adjusted for neutrophil count, there was a significant interaction between the dose of dexamethasone and time, on plasma 17R-RvD1 such that plasma 17R-RvD1 fell in a dose-dependent manner until 4 h after administration of dexamethasone. There were no significant effects of dexamethasone on the other plasma SPM (18-HEPE, RvE2, 17-HDHA, RvD1, RvD2 and 14-HDHA) measured. DiscussionThis is the first study in healthy volunteers to demonstrate that commonly employed antiemetic doses of dexamethasone affect immune cell populations and plasma levels of 17R-RvD1 an SPM with anti-nociceptive properties. If similar changes occur in surgical patients, then this may have implications for acute infection risk in the post-operative period.

Eosinophils: Old Players in a New Game.

Eosinophils are terminal polymorphonuclear cells with a high number of cytoplasmic granules that originate in bone marrow. Some are exosomes, which contain multiple molecules, such as specific eosinophilic proteins, cytokines, chemokines, enzymes, and lipid mediators that contribute to the effector role of these cells. Moreover, exosomes present a large number of receptors that allow them to interact with multiple cell types. Eosinophils play an important role in defense against infestations and are a key element in asthma and allergic diseases. Eosinophils are recruited to the inflamed area in response to stimuli, modulating the immune response through the release to the extracellular medium of their granule-derived content. Various mechanisms of degranulation have been identified. Polymorphonuclear leukocytes contain multivesicular bodies that generate exosomes that are secreted into the extracellular environment. Eosinophilic exosomes participate in multiple processes and mechanisms. Eosinophils participate actively in asthma and are hallmarks of the disease. The cells migrate to the inflammatory focus and contribute to epithelial damage and airway remodeling. Given their relevance in this pathology, new therapeutic tools have been developed that target mainly eosinophils and their receptors. In this manuscript, we provide a global, updated vision of the biology of eosinophils and the role of eosinophils in respiratory diseases, particularly asthma. We also summarize asthma treatments linked to eosinophils and new therapeutic strategies based on biological products in which eosinophils and their receptors are the main targets.

Unique Lipid Signatures of Extracellular Vesicles from the Airways of Asthmatics

Asthma is a chronic inflammatory disease process involving the conductive airways of the human lung. The dysregulated inflammatory response in this disease process may involve multiple cell-cell interactions mediated by signaling molecules, including lipid mediators. Extracellular vesicles (EVs) are lipid membrane particles that are now recognized as critical mediators of cell-cell communication. Here, we compared the lipid composition and presence of specific lipid mediators in airway EVs purified from the bronchoalveolar lavage (BAL) fluid of healthy controls and asthmatic subjects with and without second-hand smoke (SHS) exposure. Airway exosome concentrations were increased in asthmatics, and correlated with blood eosinophilia and serum IgE levels. Frequencies of HLA-DR+ and CD54+ exosomes were also significantly higher in asthmatics. Lipidomics analysis revealed that phosphatidylglycerol, ceramide-phosphates, and ceramides were significantly reduced in exosomes from asthmatics compared to the non-exposed control groups. Sphingomyelin 34:1 was more abundant in exosomes of SHS-exposed asthmatics compared to healthy controls. Our results suggest that chronic airway inflammation may be driven by alterations in the composition of lipid mediators within airway EVs of human subjects with asthma.

Resolvin D1 blocks ROS‐mediated inhibitory crosstalk between SHP2 and PP2A and suppresses endothelial‐monocyte interactions

In recent years, various studies have demonstrated a role for endogenously derived specialized lipid mediators such as resolvins in the resolution of inflammation. In exploring the signaling mechanisms, in the present study, we show that RvD1 reduces LPS‐induced endothelial cell (EC)‐monocyte interactions via blocking ROS‐mediated PP2A inactivation, NFκB activation and ICAM1 and VCAM1 expression. In addition, we found that ROS‐mediated SHP2 inhibition leads to tyrosine phosphorylation and inactivation of PP2A by LPS, which in turn, accounts for increased NFκB activation and ICAM1 and VCAM1 expression facilitating EC‐monocyte interactions and all these LPS‐mediated responses were reversed by RvD1. Furthermore, the suppression of NFκB activation, ICAM1 and VCAM1 expression and EC and monocyte interactions by RvD1 involved its receptors ALX/FPR2 and GPR32 as inhibition or neutralization of these receptors negated its effects. Together, these observations show that RvD1 via protecting SHP2 from ROS‐mediated inactivation blocks PP2A inactivation and thereby shuts of NFκB activation, ICAM1 and VCAM1 expression and EC‐monocyte interactions, which could be one of the several possible mechanisms underlying its anti‐inflammatory functions.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Aspirin-Triggered Resolvin D1-modified materials promote the accumulation of pro-regenerative immune cell subsets and enhance vascular remodeling.

This work is motivated by our efforts to explore the underlying mechanisms of inflammation resolution after injury and to develop biomaterial-based approaches to amplify endogenous mechanisms of resolution and repair. Though specific lipid mediators have been identified that actively promote the resolution of inflammation, biomaterial-based localized delivery of these mediators has been largely unexplored. We loaded Aspirin-Triggered Resolvin D1 into a PLGA scaffold and examined the effects of sustained, localized delivery on the innate immune response. We found that biomaterial delivery of resolvin was able to enhance the accumulation of pro-regenerative populations of immune cells, including anti-inflammatory monocytes, population that has never before been shown to respond to resolvin treatment, and also enhance vascular remodeling in response to tissue injury.