Resolvin Research Articles

Resolution of inflammation via RvD1/FPR2 signaling mitigates Nox2 activation and ferroptosis of macrophages in experimental abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. Resolvin D1 (RvD1) is derived from ω-3 polyunsaturated fatty acids and is involved in the resolution phase of chronic inflammatory diseases. The aim of this study was to decipher the protective role of RvD1 via formyl peptide receptor 2 (FPR2) receptor signaling in attenuating abdominal aortic aneurysms (AAA). The elastase-treatment model of AAA in C57BL/6 (WT) mice and human AAA tissue was used to confirm our hypotheses. Elastase-treated FPR2-/- mice had a significant increase in aortic diameter, proinflammatory cytokine production, immune cell infiltration (macrophages and neutrophils), elastic fiber disruption, and decrease in smooth muscle cell α-actin expression compared to elastase-treated WT mice. RvD1 treatment attenuated AAA formation, aortic inflammation, and vascular remodeling in WT mice, but not in FPR2-/- mice. Importantly, human AAA tissue demonstrated significantly decreased FPR2 mRNA expression compared to non-aneurysm human aortas. Mechanistically, RvD1/FPR2 signaling mitigated p47phox phosphorylation and prevented hallmarks of ferroptosis, such as lipid peroxidation and Nrf2 translocation, thereby attenuating HMGB1 secretion. Collectively, this study demonstrates RvD1-mediated immunomodulation of FPR2 signaling on macrophages to mitigate ferroptosis and HMGB1 release, leading to resolution of aortic inflammation and remodeling during AAA pathogenesis.

417 Resolvin D1 reduces cystic fibrosis lung disease and inflammation associated with mucus obstruction

417 Resolvin D1 reduces cystic fibrosis lung disease and inflammation associated with mucus obstruction

Targeting inflammation and pro-resolving mediators with Anetholea anisita extract to improve scalp condition.

A critical and often-overlooked factor that may give rise to dandruff and oily hair is the intrinsic quality of the scalp stratum corneum (SC), which is often unbalanced and susceptible to external aggressions. Addressing the inflammation element of unhealthy scalp plays an important role in promoting healthy-looking and feeling hair. Although specialized pro-resolving lipid mediators (SPMs) have been studied in the skin to end the inflammation process and promote tissue regeneration, no studies have been provided in the scalp. This study aims to investigate SPMs expression and its role in improving scalp integrity and consequently improving hair appearance using an Anetholea anisita extract. The effect of Anetholea anisita extract was investigated in vitro on human follicle dermal papilla cells (HFDPC), evaluating its antioxidant and anti-inflammatory properties by fluorescence staining and ELISA, respectively. Ex vivo measurement of the volume of human scalp sebaceous glands was performed using X-ray microtomography (micro-CT). The extract was then clinically tested on a population of dandruff sufferers presenting oily hair. Volunteers' sebum was collected on the scalp and analysed by LC-MS/MS or ELISA to identify SPMs and pro-inflammatory markers. Scalp integrity was assessed by measuring the pH and the TEWL. Sebum production, dandruff and hair gloss were also evaluated. Anetholea anisita extract reduced IL-8 and reactive oxygen species (ROS) generation in HFDPC. Interestingly, this extract also decreased the volume of sebaceous glands as revealed by micro-CT. This result was confirmed in vivo by a decrease in sebum production in volunteers. Moreover, SPMs were analysed and detected in the scalp for the first time. An increase in Lipoxin B4 (LxB4) and Resolvin D1 and D2 (RvD1 and RvD2) was observed after Anetholea anisita treatment as well as decrease in pro-inflammatory sebum mediators expression such as PGE2, LTB4 and IL-8. Consequently, the scalp barrier was reinforced as observed through improved transepidermal water loss (TEWL) and skin surface pH, reducing dandruff and improving hair health. The present results suggest the potential of cosmetic applications of Anetholea anisita extract to improve scalp health by targeting inflammation pathways to decrease dandruff and improve hair condition.

Evaluation of Treatment with Omega-3 Fatty Acid Supplements on Salivary Levels of Resolvin E1 in Chronic Periodontitis Patients

Abstract Context Under healthy conditions, inflammation proceeds through natural healing processes by an organized cycle. Similar to any other systemic infection, periodontal disease is also a manifestation of dysregulated inflammatory pathway.Endogenous lipid mediators called resolvins and docosatrienes, produced from omega-3 fatty acid precursors, possess various immunoregulatory properties. These polyunsaturated fatty acids cannot be synthesized in body, instead these have to be taken through diet. This study aims to evaluate the effect of adjunctive treatment with daily dietary supplementation of omega-3 fatty acids in chronic periodontitis. Aims The aim of this study was to assess periodontal parameters and salivary levels of Resolvin E1 with and without dietary supplementation of omega-3 fatty acid capsules in chronic periodontitis patients. Methods and Materials Three-month comparative clinical study was performed on 52 patients allotted to two groups, each with 26 subjects. Both groups received an initial phase 1 therapy followed by additional dietary supplementation of 500 mg of omega-3 fatty acid capsules for 3 months for the test group. Salivary levels of Resolvin E1, periodontal parameters, including pocket probing depth (PPD), clinical attachment loss (CAL), bleeding on probing (BOP), and periodontal inflamed surface area (PISA), were assessed at baseline, 1 and 3 months after the study. Statistical Analysis Used Data was analyzed with an unpaired t-test between the group and paired t-test for within the group comparison. p-Value less than 0.05 was considered significant. Results PPD and CAL showed statistically significant differences between the two groups and within the groups

Resolvin D2 uses multiple Ca2+ -dependent signaling pathways to stimulate mucin secretion in rat and human conjunctival goblet cells.

The mucin layer of the tear film is produced by goblet cells in the conjunctiva to protect the ocular surface and maintain homeostasis. The pro-resolving lipid mediator resolvin D2 (RvD2) biosynthesized from an omega 3 fatty acid actively terminates inflammation and regulates mucin secretion from conjunctival goblet cells. Our objective was to determine which Ca2+ -dependent signaling pathways RvD2 uses to stimulate conjunctival goblet cell function (CGC). We hypothesize that RvD2 activates multiple intracellular Ca2+ signaling pathways to stimulate CGC secretion. Rat and human CGCs were cultured from conjunctival explants. The amount of RvD2 receptor GPR18/DRV2 message and protein were determined. The intracellular concentration of Ca2+ ([Ca2+ ]i ) was measured in CGCs using a fluorescent Ca2+ dye and mucin secretion was determined by measuring protein secretion enzymatically with a lectin. Goblet cells were incubated with signaling pathway inhibitors before stimulation with RvD2 and [Ca2+ ]i or secretion was measured. In rat and human CGCs RvD2 receptor and in rat CGCs IP3 (a molecule that releases Ca2+ from intracellular organelles) receptors 1-3 were detected. In both species of CGC RvD2 increased [Ca2+ ]i similarly to RvD1. In rat CGCs, the increase in [Ca2+ ]i and secretion stimulated by RvD2 was significantly blocked by inhibitors to phospholipase (PL-) C and IP3 -receptor, but not protein kinase C. Increase in [Ca2+ ]i was blocked by the PLD inhibitor, but not the PLA2 inhibitor. Secretion was blocked by PLA2 inhibitor, but not the PLD inhibitor. An inhibitor of the epidermal growth factor receptor blocked the increase in [Ca2+ ]i by RvD2 in both species of CGCs. In CGCs RvD2 activates multiple intracellular signaling pathways that are Ca2+ -dependent, along with one Ca2+ -independent and one cAMP/protein kinase A-dependent pathway. Activation of these pathways stimulate mucin secretion from rat and human CGCs into the tear film contributing to ocular surface homeostasis and health.

Resolvin D1: A key endogenous inhibitor of neuroinflammation.

After the initiation of inflammation, a series of processes start to resolve the inflammation. A group of endogenous lipid mediators, namely specialized pro-resolving lipid mediators is at the top list of inflammation resolution. Resolvin D1 (RvD1), is one of the lipid mediators with significant anti-inflammatory properties. It is produced from docosahexaenoic acid (omega-3 polyunsaturated fatty acid) in the body. In this article, we aimed to review the most recent findings concerning the pharmacological effects of RvD1 in the central nervous system with a focus on major neurological diseases and dysfunctions. A literature review of the past studies demonstrated that RvD1 plasma level changes during mania, depression, and Parkinson's disease. Furthermore, RVD1 and its epimer, aspirin-triggered RvD1 (AT-RvD1), have significant therapeutic effects on experimental models of ischemic and traumatic brain injuries, memory dysfunction, pain, depression, amyotrophic lateral sclerosis, and Alzheimer's and Parkinson's diseases. Interestingly, the beneficial effects of RvD1 and AT-RvD1 were mostly induced at nanomolar and micromolar concentrations implying the significant potency of these lipid mediators in treating diseases with inflammation.

Abstract P130: Specialized Pro-resolving Mediator, Lipoxin A4, Attenuates Age-dependent Vascular Damage

Chronic, low-grade inflammation that develops with advanced age is known as inflammaging. This phenomenon is associated with large artery stiffness in age-dependent hypertension. Specialized pro-resolving mediators (SPMs), including Lipoxin A4 (LXA4) and Resolvin D1 (RD1), are derived from essential fatty acids, and they act as immunoresolvents to reduce inflammation and increase the clearance of pathogens and dying cells. However, LXA4, but not RD1, acts on formyl peptide receptor 2, which is known to modulate actin filaments and resolve inflammation. Therefore, we hypothesized that Specialized pro-resolving mediators, would restore mechanical stress and distensibility in aorta from older rats. To test this hypothesis, thoracic aortas from male Wistar rats (3 and 6 months old) were cut into 2 mm rings and incubated in the presence or absence of RD1 or LXA4; both 10 nM for 24 hours. Stress-strain curves were calculated via Tissue Puller (560TP-II, DMT). The aortic rings from 6-month-old rats presented with increased stress when compared to aortas of the 3-month-old (Maximal stress: 2749 ± 190 mN/mm 2 vs 4207 ± 242 mN/mm 2 , respectively; p=0.0015). Interestingly, LXA4 reduced stress in aorta from 6-month-old rats (Maximal stress: 2514 ± 552 mN/mm 2 , p=0.0282). No changes were observed in aorta from 3-month-old rats after LXA4 treatment. Resolvin D1 did not change vascular mechanics in aorta from 3- or 6-month-old rats. Overall, these data suggest that even modest advances in age are related with changes in vascular mechanics of large arteries and LXA4 via FPR2 can decrease inflammaging-related vascular stiffness.

Modulation of Arginase-2 mRNA Levels by ω-3 PUFAs and Aspirin in Asthmatic Human Lung Fibroblasts.

Airway remodeling (AR) increases disease severity, and morbidity of asthmatic patients by contributing to irreversible airflow obstruction and progressive declines in lung function. Arginase isoenzymes and the downstream enzymes ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT) have been implicated in the hyperplastic and fibrotic changes of AR, respectively. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and resolvin metabolites have anti-AR effects, but whether they are mediated through the arginase pathway is unclear. Our study intended to determine the effects of the ω-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), resolvin D1 (RvD1), TH1 cytokines, acetylsalicylic acid (ASA), cAMP, and dexamethasone (DEX) on the expression of arginase isoenzymes arginase 1 (ARG1) and arginase 2 (ARG2), ODC, and OAT in human lung fibroblasts (HLF) from normal (NHLF) and diseased (DHLF) asthmatic donors using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). Our data showed that EPA and EPA+DHA downregulated ARG2 mRNA 2-fold in both types of HLF. DHA, RvD1, and DEX did not alter mRNA levels for any of the genes studied. EPA lowered the ARG2 protein levels in DHLF, but did not affect those levels in NHLF. ASA upregulated ARG2 mRNA 5-fold and 7-fold in NHLF and DHLF, respectively, TH1 cytokines downregulated ARG2, ODC, and OAT mRNA in DHLF 10-fold, 2-fold, and 2.5-fold, respectively, and cAMP downregulated ARG2 mRNA 2-fold in DHLF. These results are the first to show a direct effect of ω-3 PUFAs on ARG2 mRNA levels and provide further evidence for a role of ω-3 PUFAs in AR.

Excessive inflammatory response to infection in experimental peri-implantitis: Resolution by Resolvin D2.

The aetiology and pathogenesis of peri-implantitis are currently under active research. This study aimed to dissect the pathogenesis of murine experimental peri-implantitis and assess Resolvin D2 (RvD2) as a new treatment modality. Four weeks following titanium implant insertion, mice were infected with Porphyromonas gingivalis using single or multiple oral lavages. RvD2 was administrated following infection, and tissues were analysed using flow cytometry, quantitative RT-PCR, taxonomic profiling, and micro-computed tomography. Repeated infections with Pg resulted in microbial dysbiosis and a higher influx of innate and adaptive leukocytes to the peri-implant mucosa (PIM) than to gingiva surrounding the teeth. This was accompanied by increased expression levels of IFN-α, IL-1β, and RANKL\OPG ratio. Interestingly, whereas repetitive infections resulted in bone loss around implants and teeth, a single infection induced bone loss only around implants, suggesting a higher susceptibility of the implants to infection. Treatment with RvD2 prevented Pg-driven bone loss and reduced leukocyte infiltration to the PIM. Murine dental implants are associated with dysregulated local immunity and increase susceptibility to pathogen-induced peri-implantitis. However, the disease can be prevented by RvD2 treatment, highlighting the promising therapeutic potential of this treatment modality.

First total synthesis of 4(R),17(R)-Resolvin D6 stereoisomer, a potent neuroprotective docosanoid

The first total synthesis of a novel neuroprotective Resolvin D6 enantiomer, 4(R),17(R)-Resolvin D6, is described. Resolvin D6 is a lipid mediator derived from docosahexaenoic acid (DHA, C22:6, ω-3) with anti-inflammatory properties. Key synthetic features include the use of a MacMillan enantioselective organocatalytic α-oxidation of aldehydes in conjunction with a chiral pool-based approach to generate chiral synthons, a 1,4‑enyne unit as a linchpin, as well as a (Z)-selective Wittig coupling to assemble the Resolvin D6 core carbon skeleton.

The effect of resolvin D1 on bone regeneration in a rat calvarial defect model.

Resolvin D1 (RvD1) is a pro-resolving lipid mediator of inflammation, endogenously synthesized from omega-3 docosahexaenoic acid. The purpose of this study was to investigate the effect of RvD1 on bone regeneration using a rat calvarial defect model. Collagen 3D nanopore scaffold (COL) and Pluronic F127 hydrogel (F127) incorporated with RvD1 (RvD1-COL-F127 group) or COL and F127 (COL-F127 group) were implanted in symmetrical calvarial defects. After implantation, RvD1 was administrated subcutaneously every 7days for 4weeks. The rats were sacrificed at weeks 1 and 8 post-implantation. Tissue samples were analyzed by real-time reverse transcriptase-polymerase chain reaction and histology at week 1. Radiographical and histological analyses were done at week 8. At week 1, calvarial defects treated with RvD1 exhibited decreased numbers of inflammatory cells and tartrate-resistant acid phosphatase (TRAP) positive cells, greater numbers of newly formed blood vessels, upregulated gene expression of vascular endothelial growth factor and alkaline phosphatase, and downregulated gene expression of receptor activator of nuclear factor-κB ligand, interleukin-1β and tumor necrosis factor-α. At week 8, the radiographical results showed that osteoid area fraction of the RvD1-COL-F127 group was higher than that of the COL-F127 group, and histological examination exhibited enhanced osteoid formation and newly formed blood vessels in the RvD1-COL-F127 group. In conclusion, this study showed that RvD1 enhanced bone formation and vascularization in rat calvarial defects.

Resolvin E1 attenuates doxorubicin-induced cardiac fibroblast senescence: A key role for IL-1β

Cardiac fibroblasts (CFs) undergo senescence in reaction to different stressors, leading to a poor prognosis of cardiac disease. Doxorubicin (Doxo) is an antineoplastic drug with strong cardiotoxic effects, which induces IL-1β secretion and thus, triggers a potent pro-inflammatory response. Doxo induces CFs senescence; however, the mechanisms are not fully understood. Different pharmacological strategies have been used to eliminate senescent cells by inducing their apoptosis or modifying their secretome. However, Resolvin E1 (RvE1), a lipid derivative resolutive mediator with potent anti-inflammatory effects has not been used before to prevent CFs senescence.CFs were isolated from adult male C57BL/6J mice and subsequently stimulated with Doxo, in the presence or absence of RvE1. Senescence-associated β-galactosidase activity (SA-β-gal), γ-H2A.X, p53, p21, and senescence-associated secretory phenotype (SASP) were evaluated. The involvement of the NLRP3 inflammasome/interleukin-1 receptor (IL-1R) signaling pathway on CFs senescence was studied using an NLRP3 inhibitor (MCC950) and an endogenous IL-1R antagonist (IR1A).Doxo is able to trigger CFs senescence, as evidenced by an increase of γ-H2A.X, p53, p21, and SA-β-gal, and changes in the SASP profile. These Doxo effects were prevented by RvE1. Doxo triggers IL-1β secretion, which was dependent on NLRP3 activation. Doxo-induced CFs senescence was partially blocked by MCC950 and IR1A. In addition, IL-1β also triggered CFs senescence, as evidenced by the increase of γ-H2A.X, p53, p21, SA-β-gal activity, and SASP. All these effects were also prevented by RvE1 treatment. ConclusionThese data show the anti-senescent role of RvE1 in Doxo-induced CFs senescence, which could be mediated by reducing IL-1β secretion.

Effect of Chlorogenic Acid via Upregulating Resolvin D1 Inhibiting the NF-κB Pathway on Chronic Restraint Stress-Induced Liver Inflammation.

Chronic stress can cause chronic inflammatory injury to the liver. Chlorogenic acid (CGA) is known to have a wide range of biological activities and anti-inflammatory effects. Resolvin D1 (RvD1) is a polyunsaturated fatty acid derivative that has inhibitory effects on a variety of inflammatory diseases. However, whether CGA can inhibit liver inflammation in chronic stress through RvD1 remains unclear. In this work, male rats were subjected to restraint stress for 6 h every day and built a chronic stress model for 21 days. CGA (100 mg/kg) was administered intragastrically 1 h before restraint, with intraperitoneal injection of RvD1 inhibitor WRW4 (antagonist of FPR2, 0.1 mg/kg) or WRW4 solution every 2 days for 30 min before CGA administration. CGA reduced hepatic hemorrhage and inflammatory cell infiltration, alleviated hepatic injury, decreased the activation of the NF-κB pathway and the expression of interleukin 1β, interleukin 6, and tumor necrosis factor α in the liver, and increased RvD1 in the serum and liver. The therapeutic effect of CGA was blocked after WRW4 intervention. These results suggest that the protective effects of CGA mediate the NF-κB pathway by upregulating the generation of RvD1. Above all, this research demonstrates the liver protective effect of CGA and provides a potential treatment strategy for chronic inflammatory disease.

Catechol-chitosan/polyacrylamide hydrogel wound dressing for regulating local inflammation.

Chronic wounds and the accompanying inflammation are ongoing challenges in clinical treatment. They are usually accompanied by low pH and high oxidative stress environments, limiting cell growth and proliferation. Ordinary medical gauze has limited therapeutic effects on chronic wounds, and there is active research to develop new wound dressings. The chitosan hydrogel could be widely used in biomedical science with great biocompatibility, but the low mechanical properties limit its development. This work uses polyacrylamide to prepare double-network (DN) hydrogels based on bioadhesive catechol-chitosan hydrogels. Cystamine and N, N′-Bis(acryloyl)cystamine, which can be cross-linking agents with disulfide bonds to prepare redox-responsive DN hydrogels and pH-responsive nanoparticles (NPs) prepared by acetalized cyclodextrin (ACD) are used to intelligently release drugs against chronic inflammation microenvironments. The addition of catechol groups and ACD-NPs loaded with the Resolvin E1 (RvE1), promotes cell adhesion and regulates the inflammatory response at the wound site. The preparation of the DN hydrogel in this study can be used to treat and regulate the inflammatory microenvironment of chronic wounds accurately. It provides new ideas for using inflammation resolving factor loaded in DN hydrogel of good biocompatibility with enhanced mechanical properties to intelligent regulate the wound inflammation and promote the wound repaired.

Impact of Resolvin D1 on the inflammatory phenotype of periodontal ligament cell response to hypoxia.

Periodontal ligament cells (PDLCs) are critical for wound healing and regenerative capacity of periodontal diseases. Within an inflammatory periodontal pocket, a hypoxic environment can aggravate periodontal inflammation, where PDLCs response to the inflammation would change. Resolvin D1 (RvD1) is an endogenous lipid mediator, which can impact intracellular inflammatory pathways of periodontal/oral cells and periodontal regeneration. It is not clear how hypoxia and RvD1 impact the inflammatory responses of pro-inflammatory PDLCs phenotype. Therefore, this study aimed to test hypoxia could induce changes in pro-inflammatory phenotype of PDLCs and RvD1 could reverse it. Human PDLCs were cultured from periodontal tissues from eight healthy individuals and were characterized by immunofluorescence staining of vimentin and cytokeratin. Cell viability was examined by Methyl-thiazolyl-tetrazolium (MTT) assay. To examine the effects of hypoxia and RvD1 on the inflammatory responses of pro-inflammatory PDLCs phenotype, protein levels and gene expressions of inflammatory cytokines and signal transduction molecules were measured by enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and real-time quantitative reverse transcription PCR (real-time qRT-PCR). Alizarin red S staining and real-time qRT-PCR were employed to study the effects of hypoxia and RvD1 on the osteogenic differentiation of pro-inflammatory PDLCs phenotype. It was found that hypoxia increases the expression of inflammatory factors at the gene level (p < .05). RvD1 reduced the expression of IL-1β (p < .05) in PDLCs under hypoxia both at the protein and RNA levels. There were increases in the expression of p38 mitogen-activated protein kinase (p38 MAPK, p < .01) and protein kinase B (Akt, p < .05) in response to RvD1. Also, a significantly higher density of calcified nodules was observed after treatment with RvD1 for 21 days under hypoxia. Our results indicate that hypoxia up-regulated the inflammatory level of PDLCs. RvD1 can reduce under-hypoxia-induced pro-inflammatory cytokines in the inflammatory phenotype of PDLCs. Moreover, RvD1 promotes the calcium nodules in PDLCs, possibly by affecting the p38 MAPK signaling pathway through Akt and HIF-1α.

Resolvin E1 Reduces Tumor Growth in a Xenograft Model of Lung Cancer

Inflammation plays a significant role in carcinogenesis and tumor growth. The current study was designed to test the hypothesis that resolvin E1 (RvE1) and overexpression of the receptor for RvE1 (ERV1) will prevent and/or reverse tumor generation in a gain-of-function mouse model of tumor seeding with lung cancer cells. To measure the impact of enhanced resolution of inflammation on cancer pathogenesis, ERV1-overexpressing transgenic (TG) and wild-type FVB mice were given an injection of 1×10⁶ LA-P0297 cells subcutaneously and were treated with RvE1 (100 ng; intraperitoneally) or placebo. To assess the impact of RvE1 as an adjunct to chemotherapy, ERV1-TG and wild-type FVB mice were treated with cisplatin or cisplatin + RvE1. RvE1 significantly prevented tumor growth and reduced tumor size, cyclooxygenase-2, NF-κB, and proinflammatory cytokines in TG animals as compared to wild-type animals. A significant decrease in Ki-67, vascular endothelial growth factor, angiopoietin (Ang)-1, and Ang-2 was also observed in TG animals as compared to wild-type animals. Tumor-associated neutrophils and macrophages were significantly reduced by RvE1 in transgenics (P&lt;0.001). RvE1 administration with cisplatin led to a significant reduction of tumor volume and reduced cyclooxygenase-2, NF-κB, vascular endothelial growth factor-A, Ang-1, and Ang-2. These data suggest that RvE1 prevents inflammation and vascularization, reduces tumor seeding and tumor size, and, when used as an adjunct to chemotherapy, enhances tumor reduction at significantly lower doses of cisplatin.

Enhanced silver nanoparticle-induced pulmonary inflammation in a metabolic syndrome mouse model and resolvin D1 treatment

BackgroundMetabolic syndrome (MetS) exacerbates susceptibility to inhalation exposures such as particulate air pollution, however, the mechanisms responsible remain unelucidated. Previously, we determined a MetS mouse model exhibited exacerbated pulmonary inflammation 24 h following AgNP exposure compared to a healthy mouse model. This enhanced response corresponded with reduction of distinct resolution mediators. We hypothesized silver nanoparticle (AgNP) exposure in MetS results in sustained pulmonary inflammation. Further, we hypothesized treatment with resolvin D1 (RvD1) will reduce exacerbations in AgNP-induced inflammation due to MetS.ResultsTo evaluate these hypotheses, healthy and MetS mouse models were exposed to vehicle (control) or AgNPs and a day later, treated with resolvin D1 (RvD1) or vehicle (control) via oropharyngeal aspiration. Pulmonary lung toxicity was evaluated at 3-, 7-, 14-, and 21-days following AgNP exposure. MetS mice exposed to AgNPs and receiving vehicle treatment, demonstrated exacerbated pulmonary inflammatory responses compared to healthy mice. In the AgNP exposed mice receiving RvD1, pulmonary inflammatory response in MetS was reduced to levels comparable to healthy mice exposed to AgNPs. This included decreases in neutrophil influx and inflammatory cytokines, as well as elevated anti-inflammatory cytokines.ConclusionsInefficient resolution may contribute to enhancements in MetS susceptibility to AgNP exposure causing an increased pulmonary inflammatory response. Treatments utilizing specific resolution mediators may be beneficial to individuals suffering MetS following inhalation exposures.

Gut Microbiota Alter Visceral Pain Sensation and Inflammation via Modulation of Synthesis of Resolvin D1 in Colonic Tuft Cells.

Background and AimsVisceral hypersensitivity and low grade mucosal inflammation are frequently observed in a subpopulation of irritable bowel syndrome (IBS) patients. The responsible mechanism is unclear. Resolvins are a novel class of anti-inflammatory lipid mediators that regulate resolution of inflammation and pain. We hypothesize that resolvin D1 (RvD1) synthesis is reduced in IBS-D colonic mucosa and contribute to the development of visceral hypersensitivity. MethodsWe used ELISA and qPCR to quantify the levels of RvD1 synthesis and the gene expression of LOX5 and LOX12 in colonic biopsy samples from healthy individuals (HC) or IBS-D patients. To evaluate the role of gut bacteria in regulating RvD1 synthesis, we colonized germ-free mice with different strains of bacteria, fecal microbiota from HC individuals or IBS-D patients. To evaluate the role of tuft cells in RvD1 synthesis, we examined the effect of fecal supernatant of IBS-D or HC subjects on human colonoids as well as colonoids from mice in which Chat-cre recombinase vector was used to knock-in diphtheria toxin sensitive receptor (DTRf/f) or knock-out the expression of Tlr4f/f or MyD88f/f. ResultsWe report that colonic biopsy samples from IBS-D patients generated significantly lower level of RvD1 and LOX5 mRNA. The conventionalization of germ-free mice with microbiota from IBS-D patients or gram-negative bacteria inhibited RvD1 biosynthesis and caused visceral hypersensitivity and mucosal inflammation. Colonic organoid studies demonstrate that Lps downregulated Lox5 mRNA expression and synthesis of RvD1 via Tlr4-MyD88 receptor signaling pathway in colonic tuft cells. ConclusionsOur findings indicate that RvD1 is generated in colonic tuft cells to regulate gut sensitivity to mechanical stimulation. Colonic commensal bacterial composition regulates the synthesis of RvD1 in colonic mucosa which is reduced in IBS-D patients. This appears to be mediated by elevated fecal lipopolysaccharide secondary to gram-negative gut dysbiosis.

Interferon-β regulates proresolving lipids to promote the resolution of acute airway inflammation.

Aberrant immune responses, including hyperresponsiveness to Toll-like receptor (TLR) ligands, underlie acute respiratory distress syndrome (ARDS). Type I interferons confer antiviral activities and could also regulate the inflammatory response, whereas little is known about their actions to resolve aberrant inflammation. Here we report that interferon-β (IFN-β) exerts partially overlapping, but also cooperative actions with aspirin-triggered 15-epi-lipoxin A4 (15-epi-LXA4) and 17-epi-resolvin D1 to counter TLR9-generated cues to regulate neutrophil apoptosis and phagocytosis in human neutrophils. In mice, TLR9 activation impairs bacterial clearance, prolongs Escherichia coli-evoked lung injury, and suppresses production of IFN-β and the proresolving lipid mediators 15-epi-LXA4 and resolvin D1 (RvD1) in the lung. Neutralization of endogenous IFN-β delays pulmonary clearance of E. coli and aggravates mucosal injury. Conversely, treatment of mice with IFN-β accelerates clearance of bacteria, restores neutrophil phagocytosis, promotes neutrophil apoptosis and efferocytosis, and accelerates resolution of airway inflammation with concomitant increases in 15-epi-LXA4 and RvD1 production in the lungs. Pharmacological blockade of the lipoxin receptor ALX/FPR2 partially prevents IFN-β-mediated resolution. These findings point to a pivotal role of IFN-β in orchestrating timely resolution of neutrophil and TLR9 activation-driven airway inflammation and uncover an IFN-β-initiated resolution program, activation of an ALX/FPR2-centered, proresolving lipids-mediated circuit, for ARDS.

Design and Synthesis of Cyclopropane Congeners of Resolvin E3, an Endogenous Pro-Resolving Lipid Mediator, as Its Stable Equivalents.

Resolvins are pro-resolving lipid mediators with highly potent anti-inflammatory effects. Because of their polyunsaturated structures, however, they are unstable to oxygen as a drug prototype. To address this issue, we designed and synthesized CP-RvE3 as oxidatively stable congeners of RvE3 by replacing the cis-olefin with a cis-cyclopropane to avoid the unstable bisallylic structure. Although the oxidative stabilities of CP-RvE3 were not improved, β-CP-RvE3 was 3.7 times more metabolically stable than RvE3. Thus, we identified β-CP-RvE3 as a metabolically stable equivalent.