resolvin-d1 and Disease-Models--Animal

A well-integrated host inflammatory response is essential in maintaining health and fighting disease. It is important to achieve a complete understanding of the cellular and molecular events that govern the resolution of acute inflammation. Because novel lipid-derived mediators, called resolvins and protectins in animal models, control the duration and magnitude of inflammation, the mapping of these resolution circuits may provide new ways of understanding the molecular basis of many inflammatory diseases. This article provides an overview of recent studies on resolvin and protectin biosynthesis and of advances in understanding the actions of these novel anti-inflammatory and proresolving lipid mediators. These new families of lipid-derived mediators were originally isolated from experimental murine models of acute inflammation identified during the natural spontaneous resolution phase. They are biosynthesized from omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) and possess potent anti-inflammatory, proresolving, and antifibrotic actions in vivo. Taken together, these findings suggest that defective resolution mechanisms may underlie the inflammatory phenotypes that are believed to characterize many common human diseases. The new families of endogenous proresolving and anti-inflammatory agonists constitute a new genus of anti-inflammatories.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Humans; Inflammation; Inflammation Mediators; Lipoxins

Lipid mediators are important messengers in many physiological processes. The pro-inflammatory effect of many prostaglandins, derived from the essential arachidonic acid, are well established. However, there are also anti-inflammatory lipid mediators: lipoxins and resolvins, derived from essential omega-6 and omega-3 polyunsaturated fatty acids (n-3 and n-6 PUFA), have been shown to control and resolve inflammation in a variety of experimental models of inflammatory disorders. Recent research implicates n-6 PUFA-derived lipoxins and their stable analogues as potent anti-inflammatory compounds in models of inflammatory bowel disease. Similarly, n-3 PUFA-derived lipid mediators such as resolvin E1 were shown to protect from experimental colitis in animal models. Some of their anti-inflammatory effects are mediated by dendritic cells. In this article we discuss the emerging knowledge on the effects of lipoxins and resolvins on various inflammatory pathways and why they are promising candidates for novel therapies of human inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammatory Bowel Diseases; Lipoxins; Treatment Outcome

Fungal keratitis (FK) is one of the main causes of blindness in China. People with diabetes are susceptible to corneal epithelial disease, even fungal keratitis. At present, there are few studies on this disease. Resolvins (Rv) has been reported as a mediators that exert crucial anti-inflammatory and immune regulation roles in serval diseases. In order to investigate the roles and underlying mechanism of Resolvins D1 (RvD1) on the Aspergillus fumigatus (A. fumigatus) keratitis in diabetes, we established in vivo and in vitro models of A. fumigatus keratitis, which were then exposed to high glucose. The expression levels of RvD1, 5-lipoxygenase (5-LOX), and 15-lipoxygenase (15-LOX) in A. fumigatus keratitis patients with diabetes were determined through Enzyme Linked Immunosorbent Assay (ELISA), Western blot and immunohistochemistry. Reactive Oxygen Species (ROS) production, ELISA, flow cytometry, Hematoxylin-Eosin (HE) staining and fungal loading determination were conducted to evaluate the severity of A. fumigatus infection. Lymphangiogenesis and angiogenesis were examined by immunofluorescence assay. Western blot was applied to detect the proteins of the MAPK-NF-κB pathway. The results showed that RvD1 diminished the high glucose-induced oxidative stress and inflammatory response, as evidenced by the reduction of ROS production, Interleukin-6 (IL-6), Interleukin-8 (IL-8), Heme Oxygenase-1 (HMOX-1), and the elevation of Cyclooxygenase-2 (COX2), Superoxide Dismutase (SOD-1), and Glutathione Peroxidase-2 (GPX2) levels in A. fumigatus-infected Human Corneal Endothelial Cells (HCECs). Additionally, lymphangiogenesis and angiogenesis prominently decreased after intervention with RvD1. Furthermore, RvD1 significantly reduced the levels of p-MEK1/2 and p-ERK1/2, and restrained the NF-κB and GPR32 activation. The above results showed that RvD1 protects against A. fumigatus keratitis in diabetes by suppressing oxidative stress, inflammatory response, fungal growth, and immunoreaction via modulating MAPK-NF-κB pathway. RvD1 provides clues for the therapeutic targets of Fungal keratitis complicated with diabetes.

Topics: Animals; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Aspergillosis; Aspergillus fumigatus; Blotting, Western; Cells, Cultured; Corneal Ulcer; Diabetes Complications; Disease Models, Animal; Docosahexaenoic Acids; Enzyme-Linked Immunosorbent Assay; Epithelium, Corneal; Eye Infections, Fungal; Flow Cytometry; Glucose; Humans; Immunohistochemistry; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Oxidative Stress; Oxidoreductases; Reactive Oxygen Species

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.

Topics: Animals; Carotid Arteries; Cell Movement; Disease Models, Animal; Docosahexaenoic Acids; Human Umbilical Vein Endothelial Cells; Humans; Hyperplasia; Inflammation; Mice; Neointima; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Vascular System Injuries

Intrarenal calcium oxalate (CaOx) crystals induce renal tubular epithelial cell (TEC) inflammatory and oxidative injury. This study is aimed at exploring potential therapeutic lipid components in kidney stones because lipids are involved in the development of several diseases and indicate the risk of kidney stones. Serum specimens were collected from 35 kidney stone patients and 35 normal controls. The lipid components in serum were measured, and differences were analyzed. The documented biological importance was comprehensively reviewed to identify lipids that differed significantly between the two groups to find potential agents associated with kidney stones. CaOx nephrocalcinosis mouse model was established to examine the therapeutic effects of specific lipids on CaOx deposition and CaOx-induced oxidative renal injury. Several lipids with significantly different levels were present in the serum of patients with stones and normal controls. Resolvin D1 (RvD1) (4.93-fold change,

Topics: Adult; Aged; Animals; Anti-Inflammatory Agents; Antioxidants; Calcium Oxalate; Case-Control Studies; Disease Models, Animal; Docosahexaenoic Acids; Female; Glyoxylates; Humans; Kidney Calculi; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Middle Aged; Nephrocalcinosis; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

Metabolic 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.. To 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.. Inefficient 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.

Topics: Animals; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Inflammation; Metabolic Syndrome; Metal Nanoparticles; Mice; Pneumonia; Silver

The role of resolvin D1 (RvD1) in gastroesophageal reflux disease (GERD) remains largely unknown. Here, we investigated the potential role of RvD1 in acid-induced DNA damage in esophageal epithelial cells, patients with refractory GERD and a rat model of acid reflux. Weak acid exposure induced longer comet tails, reactive oxygen species (ROS) generation, oxidative DNA damage and DNA double-strand breaks (DSBs) in cells and RvD1 (0.1 μM) blocked all these effects. Mechanistic analyses showed that apart from ROS-reducing effects, RvD1 possessed a strong capacity to promote DNA damage repair, augmenting cell cycle checkpoint activity and DSB repair by modulating phosphatase and tensin homolog (PTEN) in cells. We also detected the surface expression of formyl peptide receptor 2 (FPR2), a receptor for RvD1, in the esophageal epithelial cells, and inhibition of FPR2 abrogated the protective effects of RvD1 on cells. Furthermore, a positive correlation between RvD1 and PTEN was observed predominantly in the esophageal epithelium from patients with refractory GERD (r = 0.67, P < 0.05). Additionally, RvD1 administration upregulated PTEN, suppressed DNA DSBs and alleviated microscopic damage in the rat model of gastric reflux. FPR2 gene silencing abolished the therapeutic effects of RvD1 on the rat model. Taken together, RvD1 binding to FPR2 protects the esophageal epithelium from acid reflux-induced DNA damage via a mechanism involving the inhibition of ROS production and facilitation of DSB repair. These findings support RvD1 as a promising approach that may be valuable for the treatment of GERD.

Topics: Acids; Animals; Cell Cycle Checkpoints; Cells, Cultured; Computational Biology; Disease Models, Animal; DNA Damage; DNA Repair; Docosahexaenoic Acids; Epithelial Cells; Esophagus; Gastroesophageal Reflux; Humans; Male; Oxidative Stress; PTEN Phosphohydrolase; Rats, Sprague-Dawley; Reactive Oxygen Species

Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between proinflammatory and proresolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several proresolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 receptor exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2×ApoE double-KO background (hGPR32myc×Fpr2-/-×Apoe-/-), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2, and FOXP3. Atherosclerotic lesions, necrotic core, and aortic inflammation were reduced in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice as compared with Fpr2-/-×Apoe-/- nontransgenic littermates. In a zymosan-induced peritonitis model, the hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice had reduced inflammation at 4 hours and enhanced proresolving macrophage responses at 24 hours compared with nontransgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice, but not in Fpr2-/-×Apoe-/- nontransgenic littermates. Together, these results provide evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo.

Topics: Animals; Atherosclerosis; Disease Models, Animal; Docosahexaenoic Acids; Female; Humans; Inflammation; Macrophages; Male; Mice; Mice, Knockout, ApoE; Peritonitis; Phagocytosis; Receptors, G-Protein-Coupled; Signal Transduction

Resolvin D1 (RvD1), which is biosynthesized from essential long-chain fatty acids, is involved in anti-inflammatory activity and modulation of T cell response. Memory CD8+ T cells are important for controlling tumor growth and viral infections. Exacerbated inflammation has been described as impairing memory CD8+ T cell differentiation. This study aimed to verify the effects of RvD1 on memory CD8+ T cells in vitro and in vivo in a respiratory virus infection model. Peripheral blood mononuclear cells were treated at different time points with RvD1 and stimulated with anti-CD3/anti-CD28 antibodies. Pre-treatment with RvD1 increases the expansion of memory CD8+ T cells. The IL-12 level, a cytokine described to control memory CD8+ T cells, was reduced with RvD1 pre-treatment. When the mTOR axis was inhibited, the IL-12 levels were restored. In a respiratory virus infection model, Balb/c mice were treated with RvD1 before infection or after 7 days after infection. RvD1 treatment after infection increased the frequency of memory CD8+ T cells in the lung expressing II4, II10, and Ifng. During reinfection, RvD1-treated and RSV-infected mice present a high viral load in the lung and lower antibody response in the serum. Our results show that RvD1 modulates the expansion and phenotype of memory CD8+ T cells but contributed to a non-protective response after RSV reinfection.

Topics: Adult; Animals; Antiviral Agents; Biomarkers; CD8-Positive T-Lymphocytes; Disease Models, Animal; Docosahexaenoic Acids; Female; Host-Pathogen Interactions; Humans; Immunologic Memory; Immunophenotyping; Lymphocyte Activation; Male; Pneumovirus Infections; Reinfection; Treatment Outcome; Viral Load; Young Adult

Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor β (TGFβ), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1

Topics: Acute Kidney Injury; Albumins; Animals; Aspirin; Biomarkers; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Female; Inflammation; Kidney Function Tests; Kidney Glomerulus; Male; Mice; Mice, Inbred BALB C; Proteinuria; RNA, Messenger; Sepsis

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. In 30% of cases, after years of infection and in the absence of treatment, the disease progresses from an acute asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapeutic agent to regulate the pro-inflammatory state during the early chronic phase of Chagas disease.. C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 μg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 μg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the early chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue.. AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during early chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

Topics: Animals; Chagas Cardiomyopathy; Chronic Disease; Disease Models, Animal; Docosahexaenoic Acids; Female; Heart; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Nitroimidazoles; Parasite Load; Receptors, Formyl Peptide; Trypanosoma cruzi

Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD.. Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes.. The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Atrial Fibrillation; Atrial Remodeling; Disease Models, Animal; Docosahexaenoic Acids; Fibrosis; Heart Atria; Heart Rate; Hypertension, Pulmonary; Inflammation Mediators; Macrophages; Male; Phenotype; Rats, Wistar; Signal Transduction; Transcriptome; Ventricular Dysfunction, Right

Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown.. The effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca. RvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3-30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca. Our data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS.

Topics: Adult; Animals; Capsaicin; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Enterobacteriaceae Infections; Female; Ganglia, Spinal; Histamine; Humans; Hypersensitivity; Inflammation; Irritable Bowel Syndrome; Male; Mice; Middle Aged; Neurons; Rats; Receptors, Cannabinoid; TRPV Cation Channels

Excessive inflammation is a major cause contributing to early brain injury (EBI) and is associated with negative or catastrophic outcomes of subarachnoid hemorrhage (SAH). Resolvin D1 (RvD1) exerts strong anti-inflammatory and pro-resolving effects on either acute or chronic inflammation of various origin. Henceforth, we hypothesized that RvD1 potentially attenuates excessive inflammation in EBI following SAH. Therefore, we generated a filament perforation SAH model and administered 3 different doses (0.3, 0.6, and 1.2 nmol) of RvD1 after experimental SAH. Neurological scores, brain edema, and blood-brain barrier integrity were evaluated; besides, neutrophil infiltration, neuronal deaths, and microglial pro-inflammatory polarization were observed using histopathology or immunofluorescence staining, western blots, and qPCR. After confirming the effectiveness of RvD1 in SAH, we administered the FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4) 30 min before SAH establishment to observe whether this compound could abolish the anti-inflammatory effect of RvD1. Altogether, our results showed that RvD1 exerted a strong anti-inflammatory effect and markedly reduced neutrophil infiltration and microglial pro-inflammatory activation, leading to remarkable improvements in neurological function and brain tissue restoration. After addition of WRW4, the anti-inflammatory effects of RvD1 were abolished. These results indicated that RvD1 could exert a good anti-inflammatory effect and alleviate EBI, which suggested that RvD1 might be a novel therapeutic alternative for SAH-induced injury.

Topics: Animals; Anti-Inflammatory Agents; Blood-Brain Barrier; Brain; Brain Edema; Disease Models, Animal; Docosahexaenoic Acids; Immunity, Innate; Oligopeptides; Rats; Receptors, Formyl Peptide; Signal Transduction; Subarachnoid Hemorrhage

Cigarette smoke is a potent proinflammatory trigger contributing to acute lung injury and the development of chronic lung diseases via mechanisms that include the impairment of inflammation resolution. We have previously demonstrated that secondhand smoke (SHS) exposure exacerbates bacterial infection-induced pulmonary inflammation and suppresses immune responses. It is now recognized that resolution of inflammation is a bioactive process mediated by lipid-derived specialized proresolving mediators that counterregulate proinflammatory signaling and promote resolution pathways. We therefore hypothesized that proresolving mediators could reduce the burden of inflammation due to chronic lung infection following SHS exposure and restore normal immune responses to respiratory pathogens. To address this question, we exposed mice to SHS followed by chronic infection with nontypeable

Topics: Animals; Antibodies, Bacterial; Disease Models, Animal; Docosahexaenoic Acids; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Lung; Mice; Pneumonia; Tobacco Smoke Pollution

Resolvin D1, a specialized pro-resolving lipid mediator produced from docosahexaenoic acid by 15- and 5-lipoxygenase, exerts anti-inflammatory effects driving to the resolution of inflammation. The present study aimed to elucidate its role in small intestinal damage induced by nonsteroidal anti-inflammatory drug (NSAID). Indomethacin was administered orally to C57BL/6J male mice, which were sacrificed 24 h later to collect small intestine specimens. Before administration of indomethacin, mice were subjected to intraperitoneal treatment with resolvin D1 or oral administration of baicalein, a 15-lipoxygenase inhibitor. Small intestinal damage induced by indomethacin was attenuated by pretreatment with resolvin D1. Furthermore, resolvin D1 reduced the gene expression levels of interleukin-1β, tumor necrosis factor-α, and CXCL1/keratinocyte chemoattractant. Conversely, the inhibition of 15-lipoxygenase activity by baicalein increased the expression of genes coding for these inflammatory cytokines and chemokine, leading to exacerbated small intestinal damage, and reduced the concentration of resolvin D1 in the small intestinal tissue. Exogenous treatment with resolvin D1 negated the deleterious effect of baicalein. 15-lipoxygenase was mainly expressed in the epithelium and inflammatory cells of the small intestine, and its gene and protein expression was not affected by the administration of indomethacin. Inhibition of the resolvin D1 receptor, lipoxin A4 receptor /formyl peptide receptor 2, by its specific inhibitors Boc-1 and WRW4 aggravated indomethacin-induced small intestinal damage. Collectively, these results indicate that resolvin D1 produced by 15-lipoxygenase contributes to mucoprotection against NSAID-induced small intestinal damage through its anti-inflammatory effect.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 15-Lipoxygenase; Chemokine CXCL1; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Drug-Related Side Effects and Adverse Reactions; Inflammation; Intestinal Mucosa; Intestine, Small; Lipids; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred C57BL; Pharmaceutical Preparations; Protective Agents

To evaluate whether allergic conjunctivitis (AC) could be induced by. Human conjunctival epithelial cells (HCVCs) were treated with 10 µg/well of ESP, and Th2 cytokines were measured using real-time PCR. C57BL/6 mice were treated with 10 µg/5 µL of ESP after sensitization, and conjunctivas isolated from the mice were stained with hematoxylin and eosin (H&E) for the analysis of eosinophils and periodic acid-Schiff (PAS) for the analysis of goblet cells. Cytokine levels in the eye-draining lymph nodes (dLNs) and spleens were measured using the enzyme-linked immunosorbent assay (ELISA). Then, the treatment effects of RvD1 and the antiallergic agents (olopatadine, bepotastine, and alcaftadine) on the HCVCs, mouse conjunctivas, dLNs, and spleens were assessed.. Th2 cytokines were increased in the ESP-treated conjunctival cells. Mouse conjunctivas treated with ESP showed significant infiltration of eosinophils and goblet cells, and the dLN and spleen exhibited increased IL-4, IL-5 and IL-13 levels. All findings were significantly decreased upon treatment with RvD1 and the antiallergic agents.

Topics: Acanthamoeba; Animals; Cell Line; Conjunctiva; Conjunctivitis, Allergic; Disease Models, Animal; Docosahexaenoic Acids; Female; Humans; Mice; Mice, Inbred C57BL; Protozoan Proteins

Despite the broad pharmacological arsenal to treat hypertension, chronic patients may develop irreversible cardiac remodeling and fibrosis. Angiotensin II, the main peptide responsible for the Renin-Angiotensin-Aldosterone-System, has been closely linked to cardiac remodeling, hypertrophy, fibrosis, and hypertension, and some of these effects are induced by inflammatory mediators. Resolvin-D1 (RvD1) elicits potent anti-inflammatory and pro-resolving effects in various pathological models. In this study, we aimed to examine whether RvD1 ameliorates cardiac remodeling and hypertension triggered by angiotensin II.. Alzet® osmotic mini-pumps filled with angiotensin II (1.5 mg/kg/day) were implanted in male C57BL/6 J mice for 7 or 14 days. RvD1 (3 μg/kg/day, i.p) was administered one day after the surgery and during the complete infusion period. Blood pressure and myocardial functional parameters were assessed by echocardiography. At the end of the experimental procedure, blood and heart tissue were harvested, and plasma and histological parameters were studied. After 7 and 14 days, RvD1 reduced the increase of neutrophil and macrophage infiltration triggered by angiotensin II, and also reduced ICAM-1 and VCAM-1 expression levels. RvD1 also reduced cytokine plasma levels (IL-1β, TNF-α, IL-6, KC, MCP-1), cardiac hypertrophy, interstitial and perivascular fibrosis, and hypertension.. This study unveils novel cardioprotective effects of RvD1 in angiotensin II-induced hypertension and cardiac remodeling by attenuating inflammation and provides insights into a potential clinical application.

Topics: Angiotensin II; Animals; Cardiomegaly; Chemokine CCL2; Disease Models, Animal; Docosahexaenoic Acids; Gene Expression Regulation; Humans; Hypertension; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Mice; Renin-Angiotensin System; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Ventricular Remodeling

To evaluate the potential changes in the plasma levels of resolvin D1 (RvD1) in patients with trauma and hemorrhage. Having found that trauma results in a profound reduction in plasma RvD1 in patients, we have then investigated the effects of RvD1 on the organ injury and dysfunction associated with hemorrhagic shock (HS) in the rat.. HS is a common cause of death in trauma due to excessive systemic inflammation and multiple organ failure. RvD1 is a member of the resolvin family of pro-resolution mediators.. Blood samples were drawn from critically injured patients (n = 27, ACITII-prospective observational cohort study) within 2 hours of injury for targeted liquid chromatography tandem mass spectrometry. HS rats (removal of blood to reduce arterial pressure to 30 ± 2 mm Hg, 90 minutes, followed by resuscitation) were treated with RvD1 (0.3 or 1 μg/kg intravenous (i.v.)) or vehicle (n = 7). Parameters of organ injury and dysfunction were determined.. Plasma levels of RvD1 (mg/dL) were reduced in patients with trauma+HS (0.17 ± 0.08) when compared with healthy volunteers (0.76 ± 0.25) and trauma patients (0.62 ± 0.20). In rats with HS, RvD1 attenuated the kidney dysfunction, liver injury, and tissue ischemia. RvD1 also reduced activation of the nuclear factor (NF)-κB pathway and reduced the expression of pro-inflammatory proteins such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β, and interleukin-6.. Plasma RvD1 is reduced in patients with trauma-HS. In rats with HS, administration of synthetic RvD1 on resuscitation attenuated the multiple organ failure associated with HS by a mechanism that involves inhibition of the activation of NF-κB.

Topics: Animals; Biomarkers; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Immunohistochemistry; Male; Multiple Organ Failure; Rats; Rats, Wistar; Shock, Hemorrhagic

Inflammation ensuing from vascular injury promotes intimal hyperplasia (IH) and restenosis. Resolvin D1 (RvD1) is a lipid mediator that attenuates IH in vivo when delivered locally to the vessel wall in animal models. We tested the hypothesis that peri-procedural oral administration of RvD1 could blunt the local inflammatory response to angioplasty, and attenuate downstream IH. Carotid angioplasty was performed on rats fed with either RvD1 or vehicle through oral gavage, starting one day prior to injury until post-operative day (POD) 3 or 14 when arteries were harvested. To study pharmacokinetics and bioactivity of oral RvD1, we measured plasma RvD1 by ELISA, whole blood phagocytosis activity using flow cytometry, and cAMP levels in the thoracic aorta by ELISA. Carotid arteries were harvested on POD3 for staining (anti-CD45, anti-Myeloperoxidase (MPO), anti-Ki67 or dihydroethidium (DHE) for reactive oxygen species), mRNA expression of target genes (quantitative RT-PCR), or on POD14 for morphometry (elastin stain). RvD1 plasma concentration peaked 3 h after gavage in rats, at which point we concurrently observed an increase in circulating monocyte phagocytosis activity and aortic cAMP levels in RvD1-treated rats vs. vehicle. Oral RvD1 attenuated local arterial inflammation after angioplasty by reducing CD45+, MPO+, Ki67+ cells, and DHE staining intensity. Oral RvD1 also reduced the expression of several pro-inflammatory genes within the injured vessels. However, oral RvD1 did not significantly reduce IH. Oral RvD1 attenuated acute inflammation within the arterial wall after angioplasty in rats, but did not significantly affect IH.

Topics: Administration, Oral; Angioplasty; Animals; Carotid Arteries; Disease Models, Animal; Docosahexaenoic Acids; Hyperplasia; Inflammation; Male; Rats; Rats, Sprague-Dawley; Tunica Intima

Following global ischemia reperfusion injury triggered by cardiac arrest (CA) and resuscitation, the ensuing cardiac and cerebral damage would result in high mortality and morbidity. Recently, resolvin D1 has been proven to have a protective effect on regional cardiac and cerebral ischemia reperfusion injury. In this study, we investigated the effects of resolvin D1 on cardiac and cerebral outcomes after cardiopulmonary resuscitation (CPR) in a porcine model.Twenty-eight male domestic pigs weighing between 33 and 41 kg were randomly divided into one of the four groups: sham, CPR, low-dose resolvin D1 (LRD), and high-dose resolvin D1 (HRD). Sham animals underwent the surgical preparation only. Other animals were subjected to 8 min of untreated ventricular fibrillation and then 5 min of CPR. At 5 min after resuscitation, resolvin D1 was intravenously administered with the doses of 0.3 and 0.6 μg/kg in the LRD and HRD groups, respectively. The resuscitated animals were monitored for 6 h and observed for an additional 18 h.After resuscitation, myocardial and neurological function were significantly impaired, and their serum levels of injury biomarkers were markedly increased in the CPR, LRD, and HRD groups compared with the sham group. In addition, tissue inflammation and oxidative stress in the heart and brain were observed in the three groups. However, myocardial function was significantly improved and its injury biomarker was significantly decreased starting 3 h after resuscitation in the LRD and HRD groups compared with the CPR group. Similarly, neurological function was significantly better at 24 h post-resuscitation and its injury biomarkers were significantly lower at 6 and 24 h post-resuscitation in the LRD and HRD groups than in the CPR group. In addition, myocardial, cerebral inflammation, and oxidative stress were significantly milder in the two resolvin D1-treated groups. Especially, HRD produced significantly greater post-resuscitation cardiac and cerebral protection compared with the LRD group.In conclusion, resolvin D1 significantly improved post-resuscitation cardiac and cerebral outcomes in a porcine model of CA, in which the protective effects may be in a dose-dependent manner.

Topics: Animals; Cardiopulmonary Resuscitation; Disease Models, Animal; Docosahexaenoic Acids; Heart Arrest; Male; Monitoring, Physiologic; Swine; Ventricular Fibrillation

Sjögren's syndrome (SS) is an autoimmune disease that causes chronic inflammation of the salivary glands leading to secretory dysfunction. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) reduces inflammation and restores tissue integrity in salivary glands. Specifically, progression of SS-like features in NOD/ShiLtJ mice can be systemically halted using AT-RvD1 prior or after disease onset to downregulate proinflammatory cytokines, upregulate anti-inflammatory molecules, and restore saliva production. Therefore, the goal of this paper was to create a physiologically based pharmacokinetic (PBPK) model to offer a reasonable starting point for required total AT-RvD1 dosage to be administered in future mice and humans thereby eliminating the need for excessive use of animals and humans in preclinical and clinical trials, respectively. Likewise, PBPK modeling was employed to increase the range of testable scenarios for elucidating the mechanisms under consideration.. Pharmacokinetics following intravenous administration of a 0.1 mg/kg dose of AT-RvD1 in NOD/ShiLtJ were predicted in both plasma and saliva using PBPK modeling with PK-Sim® and MoBi® Version 7.4 software.. The model provides high-value pathways for future validation via in vivo studies in NOD/ShiLtJ to corroborate the findings themselves while also establishing this method as a means to better target drug development and clinical study design.. Clinical and basic research would benefit from knowledge of the potential offered by computer modeling. Specifically, short-term utility of these pharmacokinetic modeling findings involves improved targeting of in vivo studies as well as longer term prospects for drug development and/or better designs for clinical trials.

Topics: Administration, Intravenous; Animals; Aspirin; Clinical Trials as Topic; Computer Simulation; Disease Models, Animal; Docosahexaenoic Acids; Drug Dosage Calculations; Drug Evaluation, Preclinical; Humans; Mice; Models, Biological; Saliva; Salivary Glands; Sjogren's Syndrome; Tissue Distribution

Our previous results showed that the specialized pro-resolving mediator (SPM) Resolvin D1 (RvD1) promotes resolution of inflammation in salivary glands in non-obese diabetic (NOD)/ShiLtJ, a mouse model for Sjögren's syndrome (SS). Additionally, mice lacking the RvD1 receptor ALX/FPR2 show defective innate and adaptive immune responses in salivary glands. Particularly, ALX/FPR2 KO mice exhibit exacerbated inflammation in their salivary glands in response to systemic LPS treatment. Moreover, female ALX/FPR2 KO mice show increased autoantibody production and loss of salivary gland function with age. Together, these studies suggest that an underlying SPM dysregulation could be contributing to SS progression. Therefore, we investigated whether SPM production is altered in NOD/ShiLtJ using metabololipidomics and enzyme-linked immunosorbent assay (ELISA). Our results demonstrate that SPM levels were broadly elevated in plasma collected from NOD/ShiLtJ female mice after disease onset, whereas these drastic changes did not occur in male mice. Moreover, gene expression of enzymes involved in SPM biosynthesis were altered in submandibular glands (SMG) from NOD/ShiLtJ female mice after disease onset, with 5-LOX and 12/15-LOX being downregulated and upregulated, respectively. Despite this dysregulation, the abundances of the SPM products of these enzymes (ie, RvD1 and RvD2) were unaltered in freshly isolated SMG cells suggesting that other cell populations (eg, lymphocytes) may be responsible for the overabundance of SPMs that we observed. The elevation of SPMs noted here appeared to be sex mediated, meaning that it was observed only in one sex (females). Given that SS primarily affects females (roughly 90% of diagnosed cases), these results may provide some insights into the mechanisms underlying the observed sexual dimorphism.

Topics: Adaptor Proteins, Signal Transducing; Animals; Disease Models, Animal; Docosahexaenoic Acids; Down-Regulation; Female; Inflammation; Male; Mice; Mice, Inbred NOD; Mice, Knockout; Receptors, Formyl Peptide; Salivary Glands; Sex Factors; Sjogren's Syndrome; Submandibular Gland; Up-Regulation

Nonalcoholic fatty liver disease (NAFLD) is becoming a major public health problem worldwide. The study aimed to evaluate the concentration of eicosanoids in serum and liver tissue during steatosis progression and to assess whether eicosanoid change scores may predict liver tissue remodeling. Thirty six eight-week-old male Sprague Dawley rats were enrolled and sacrificed at different stages of NAFLD. Eicosanoid concentrations, namely lipoxin A

Topics: Animals; Biomarkers; Chromatography, Liquid; Dinoprostone; Disease Models, Animal; Disease Progression; Docosahexaenoic Acids; Eicosanoids; Eicosapentaenoic Acid; Hydroxyeicosatetraenoic Acids; Linoleic Acids; Lipoxins; Liver; Male; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley

Topics: Animals; Cells, Cultured; Disease Models, Animal; Docosahexaenoic Acids; Female; Gene Knockout Techniques; Humans; Ischemia; Macrophages; Male; Mice; Mice, Knockout; Muscle, Skeletal; Neovascularization, Physiologic; Primary Cell Culture; Receptors, Formyl Peptide; Receptors, Lipoxin; RNA-Seq; Signal Transduction; Skin; Transcription, Genetic; Wound Healing

Agricultural workers are at risk for the development of acute and chronic lung diseases due to their exposure to organic agricultural dusts. A diet intervention using the omega-3 fatty acid docosahexaenoic acid (DHA) has been shown to be an effective therapeutic approach for alleviating a dust-induced inflammatory response. We thus hypothesized a high-DHA diet would alter the dust-induced inflammatory response through the increased production of specialized pro-resolving mediators (SPMs). Mice were pre-treated with a DHA-rich diet 4 weeks before being intranasally challenged with a single dose of an extract made from dust collected from a concentrated swine feeding operation (HDE). This omega-3-fatty-acid-rich diet led to reduced arachidonic acid levels in the blood, enhanced macrophage recruitment, and increased the production of the DHA-derived SPM Resolvin D1 (RvD1) in the lung following HDE exposure. An assessment of transcript-level changes in the immune response demonstrated significant differences in immune pathway activation and alterations of numerous macrophage-associated genes among HDE-challenged mice fed a high DHA diet. Our data indicate that consuming a DHA-rich diet leads to the enhanced production of SPMs during an acute inflammatory challenge to dust, supporting a role for dietary DHA supplementation as a potential therapeutic strategy for reducing dust-induced lung inflammation.

Topics: Animal Feed; Animals; Arachidonic Acid; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Dust; Inhalation Exposure; Lung; Male; Mice; Mice, Inbred C57BL; Pneumonia; Swine

Topics: Animals; Anti-Inflammatory Agents; Chorioamnionitis; Disease Models, Animal; Disease Susceptibility; Docosahexaenoic Acids; Female; Gene Expression; Humans; Immunohistochemistry; Lipopolysaccharides; Mice; Mice, Knockout; NF-kappa B; Placenta; PPAR gamma; Pregnancy; Receptors, Formyl Peptide; Signal Transduction; Trophoblasts

The aim of this study was to investigate the effects of the lipid mediator Resolvin D1 in experimental keratitis. C57BL/6J mice were injected with lipopolysaccharide (2 µg/eye), and after 24 hours, the corneal damage was assessed. Clinical score was quantified, and corneal inflammatory biomarkers were detected by immunohistochemistry. A robust accumulation of sub-epithelial macrophages and polymorphonuclear leucocytes, chemokine (C-X-C motif) ligand 1 (also known as keratinocyte-derived chemokine), interleukin-10 and promoters of apoptosis was also observed in lipopolysaccharide-treated mice. Formyl peptide receptor 2 corneal expression was also assessed. The corneal stroma treated with lipopolysaccharide was characterized by presence of macrophages of M1-like subtype and immature fibroblastic cells, marked with Ki67, not fully differentiated in fibroblasts. Indeed, the staining of the cornea with anti-vimentin antibodies, a marker of differentiated myofibroblasts, was very faint. Resolvin D1 attenuated all the inflammatory parameters assessed in the present study, except for IL-10. In conclusion, the data presented here seem to be consistent with the hypothesis that Resolvin D1 protected the cornea from the lipopolysaccharide-induced keratitis by acting on several inflammatory components of this damage, pivoted by Formyl peptide receptor 2 (FPR2) activation and macrophages-leucocytes activity.

Topics: Animals; Apoptosis; Connexin 43; Cornea; Corneal Stroma; Disease Models, Animal; Docosahexaenoic Acids; Fibroblasts; Immunohistochemistry; Inflammation; Interleukin-10; Keratitis; Ki-67 Antigen; Leukocytes; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Phenotype; Vimentin

Neuroinflammation is one of the hallmarks of Parkinson's disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD - to modulate disease progression - still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Docosahexaenoic Acids; Dopaminergic Neurons; Humans; Inflammation; Male; Microglia; Nerve Degeneration; Parkinson Disease; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Substantia Nigra

Severe, chronic eye allergy is an understudied, vision-threatening condition. Treatments remain limited. We used a mouse model of severe allergic eye disease (AED) to determine whether topical application of the pro-resolution mediator Resolvin D1 (RvD1) terminates the response. AED was induced by injection of ovalbumin (OVA) followed by topical challenge of OVA daily. RvD1 was applied topically prior to OVA. Clinical symptoms were scored. Eye washes were assayed for MUC5AC. After 7 days, eyes were removed and the number of goblet cells, T helper cell responses and presence of immune cells in draining lymph nodes and conjunctiva determined. Topical RvD1 treatment significantly reduced symptoms of AED. RvD1 did not alter the systemic type 2 immune response in the lymph nodes. AED increased the total amount of goblet cell mucin secretion, but not the number of goblet cells. RvD1 prevented this increase, but did not alter goblet cell number. Absolute numbers of CD4 + T cells, total CD11b + myeloid cells, eosinophils, neutrophils, and monocytes, but not macrophages increased in AED versus RvD1-treated mice. We conclude that topical application of RvD1 reduced the ocular allergic response by local actions in conjunctival immune response and a decrease in goblet cell mucin secretion.

Topics: Allergens; Animals; Cells, Cultured; Chronic Disease; Disease Models, Animal; Docosahexaenoic Acids; Eye Diseases; Goblet Cells; Humans; Hypersensitivity; Immunity, Cellular; Mice; Mice, Inbred C57BL; Mucin 5AC; Ovalbumin

Specialized proresolving mediators from ω-3 polyunsaturated fatty acid may control resolution of inflammation. We evaluated the influence of two specialized proresolving mediators, resolvin D1 (RvD1) and protectin D1 isomer (PD1 iso) on neointimal hyperplasia after balloon injury.. Sprague Dawley male rats at 12-14 wk of age were injured as a model of balloon angioplasty. Then, 1 μg/rat of RvD1 or PD1 iso was administered intravenously via the tail vein immediately and 2 d after angioplasty. The proliferation of injured artery and the infiltration of leukocytes, monocytes, and macrophages at 3 d after injury were evaluated by immunostaining. The activity of the inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) in the injured artery at 3 d after injury was evaluated using an enzyme-linked immuno sorbent assay kit. The proliferation of the neointima was evaluated by calculating the ratio of the neointimal and medial areas using specimens at 14 d after injury.. RvD1 and PD1 iso attenuated proliferation of medial cells (P < 0.05) and infiltration of leukocytes (P < 0.05) and monocytes/macrophages (P < 0.01). Although both RvD1 and PD1 iso mitigated NFκB activity (P < 0.01), RvD1 attenuated this activity more strongly (P < 0.01). RvD1 decreased neointimal hyperplasia by 37.3% (P < 0.01), whereas PD1 iso decreased neointimal hyperplasia by 31.8% (P < 0.05) (RvD1 versus PD1 iso: P = 0.51).. RvD1 and PD1 iso reduced the activity of inflammatory transcription factor NFκB within the injured artery and attenuated inflammatory cell infiltration, leading to a reduction in early inflammation and subsequent neointimal hyperplasia.

Topics: Angioplasty, Balloon; Animals; Carotid Arteries; Carotid Artery Injuries; Disease Models, Animal; Docosahexaenoic Acids; Humans; Hyperplasia; Injections, Intravenous; Male; Neointima; NF-kappa B; Rats; Rats, Sprague-Dawley; Treatment Outcome; Tunica Intima

Non-resolved persistent macrophage-mediated synovial inflammation is considered as one of the main drivers of both the establishment and progression of obesity-associated osteoarthritis (OA). Herein, we used clodronate-loaded liposomes (CL) to locally deplete macrophages in the synovial joints to examine the role of macrophages in the progression of obesity-induced OA. Furthermore, resolvin D1 (RvD1), a unique family of pro-resolving lipid mediator derived from the omega-3 polyunsaturated fatty acid, have shown marked potency in changing the pro-inflammatory behaviour of the macrophages. We sought to determine whether RvD1 administration ameliorates obesity-induced OA by resolving macrophage-mediated synovitis. Therapeutic properties of RvD1 and macrophage depletion (CL) were tested for its ability to slow post-traumatic OA (PTOA) in obese mice models. PTOA was induced in C57Bl/6 mice fed with high-fat diet (HFD) by surgically destabilising the meniscus. Firstly, CL treatment showed beneficial effects in reducing synovitis and cartilage destruction in obese mice with PTOA. In vitro treatment with RvD1 decreased the levels of pro-inflammatory markers in CD14+ human macrophages. Furthermore, intra-articular treatment with RvD1 diminishes the progression of OA in the knee joint from mice as follows: (a) decreases macrophages infiltration in synovium, (b) reduces the number of pro-inflammatory macrophages in synovium and (c) improves the severity of synovitis and cartilage degradation. Thus, our results provide new evidence for the potential targeting of macrophages in the treatment of obesity-induced OA.

Topics: Animals; Dietary Fats; Disease Models, Animal; Docosahexaenoic Acids; Humans; Inflammation Mediators; Macrophages; Male; Mice; Obesity; Osteoarthritis; Synovial Membrane

Topics: Animals; Antineoplastic Agents; Aspirin; Chemokine CCL2; Chemokines; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Eicosanoids; Fatty Acids, Unsaturated; Female; Inflammation; Lipoxins; Macrophages; Metabolomics; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neoplasm Metastasis; Neoplasms; Nerve Tissue Proteins; Phagocytosis; Plasminogen Inactivators; Prostaglandins

SS is characterized by chronic inflammation of the salivary glands leading to loss of secretory function, thereby suggesting specialized pro-resolving mediators targeting inflammation to be a viable option for treating SS. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) prevents chronic inflammation and enhances saliva secretion in a SS-like mouse model when applied before disease onset. However, this therapy cannot be used in SS patients given that diagnosis occurs post-disease onset and no reliable screening methods exist. Therefore, we examined whether treatment with AT-RvD1 reduces SS-like features in a mouse model post-disease onset.. Tail vein injections were performed in a SS-like mouse model both with and without AT-RvD1 post-disease onset for 8 weeks, with salivary gland function and inflammatory status subsequently determined.. Treatment of a SS-like mouse model with AT-RvD1 post-disease onset restores saliva secretion in both females and males. Moreover, although AT-RvD1 treatment does not reduce the overall submandibular gland lymphocytic infiltration, it does reduce the number of T helper 17 cells within the infiltrates in both sexes. Finally, AT-RvD1 reduces SS-associated pro-inflammatory cytokine gene and protein expression levels in submandibular glands from female but not male mice.. AT-RvD1 treatment administered post-disease onset reduces T helper 17 cells and successfully restores salivary gland function in a SS mouse model with variable effects noted by sex, thus warranting further examination of both the causes for the sex differences and the mechanisms responsible for the observed treatment effect.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Drug Evaluation, Preclinical; Female; Inflammation Mediators; Lymphocyte Count; Male; Mice, Inbred NOD; Saliva; Salivation; Sjogren's Syndrome; Th17 Cells

Resolvin D1 (RvD1), a pro-resolution lipid mediator derived from docosahexaenoic acid (DHA), has been described to promote several kinds of inflammatory resolution. However, the effects and anti-inflammatory mechanisms of RvD1 on psoriasis have not been previously reported.. The present study aimed to determine the protective effects and the underlying mechanisms of RvD1 on imiquimod (IMQ)-induced psoriasiform dermatitis.. Mice were topically treated with IMQ to develop psoriasiform dermatitis on their shaved back, pretreated intraperitoneally (i.p.) with or without RvD1 or tert-butoxycarbonyl Met-Leu-Phe peptide (Boc), a lipoxin A4 (ALX) receptor antagonist. The severity was monitored and graded using a modified human scoring system, the Psoriasis Area and Severity Index (PASI), histopathology, and the signature cytokines of psoriasis (IL-23, IL-17, IL-22 and TNF-α). The mRNA and protein levels of inflammatory cytokines were quantified by quantitative real-time PCR (QRT-PCR) and ELISA. The expressions of signaling proteins MAPKs and NF-κB p65 were analyzed using western blotting. Electrophoretic mobility shift assay (EMSA) was used to check NF-κB p65 DNA binding activity.. Our study showed that RvD1 alleviated IMQ-induced psoriasiform dermatitis and improved skin pathological changes. RvD1 markedly inhibited IMQ-induced activation of ERK1/2, p38, JNK (c-Jun N-terminal protein kinase, a subfamily of MAPKs), and NF-κB. Furthermore, pretreatment with Boc, would not exacerbate skin inflammation of IMQ-induced mice, but significantly reversed the beneficial effects of RvD1 on IMQ-induced psoriasiform inflammation.. RvD1 can obviously improve skin inflammation in IMQ-induced mice psoriasiform dermatitis. The protective mechanisms might be related to its selective reaction with lipoxin A4 receptor/Formyl-peptide receptor 2 (ALX/FPR2), by downregulating relevant cytokines of the IL-23/IL-17 axis expression, the inhibition of MAPKs and NF-κB signaling transduction pathways. Thus, these results show that RvD1 could be a possible candidate for psoriasis therapy.

Topics: Administration, Cutaneous; Aminoquinolines; Animals; Anti-Inflammatory Agents; Dermatitis; Disease Models, Animal; Docosahexaenoic Acids; Drug Evaluation, Preclinical; Humans; Imiquimod; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; Psoriasis; Severity of Illness Index; Signal Transduction; Skin; Skin Cream

Long-term exposure to cigarette smoke (CS) results in alveolar parenchyma destruction due to chronic inflammatory response and the imbalance between oxidants and antioxidants, and proteases and antiproteases. Emphysema is the main symptom of chronic obstructive pulmonary disease. Current treatment focuses on relieving respiratory symptoms, and inflammation resolution failure is an important pathophysiological element of the disease. Specialized pro-resolving mediators (SPMs) synthesized endogenously during resolution processes demonstrated beneficial effects in murine models of airway inflammation. Here, we aimed to test the SPM AT-RvD1 in a murine model of CS-induced emphysema. AT-RvD1 restored elastic fibers and lung morphology, with reduction in MMP-3, neutrophils, and myeloperoxidase activity and increases in macrophages and IL-10 levels. AT-RvD1 also decreased levels of oxidative stress markers and ROS via upregulation of the Nrf2/Keap1 pathway. Therefore, we suggest that AT-RvD1 causes pro-resolutive action in our murine model of CS-induced emphysema by upregulation of the Nrf2/Keap1 pathway.

Topics: Animals; Anti-Inflammatory Agents; Cigarette Smoking; Disease Models, Animal; Docosahexaenoic Acids; Emphysema; Humans; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Signal Transduction

Acute pancreatitis (AP) is a common acute gastrointestinal disorders. Increasing evidence indicated that autophagy is involved in the development of AP. Resolvin D1 is an endogenous pro-resolving lipid mediator, which can protect mice from cerulein-induced acute pancreatitis and facilitate autophagy in macrophage, but its mechanism remians unclear.. To investigate the effect of resolvin D1 on autophagy in mouse models of cerulein-induced AP.. C57BL/6 mice were randomly divided into control group, AP group and resolvin D1 group. The models of cerulein-induced AP were constructed by intraperitoneally cerulein. Resolvin D1 group was established by intraperitoneally resolvin D1 based on AP models, simultaneously, control group received normal saline. The severity of AP, the level of inflammatory cytokines, the number of autophagic vacuoles, and the expression of autophagy-related markers were evaluated among three groups.. The AP models were established successfully. Compared to control group, the number of autophagic vacuoles and expressions of autophagy-related markers including Beclin-1, p62 and LC3-II were increased in AP models, In contrast, the degree of inflammation and levels of inflammatory cytokines in AP models were reduced after resolvin D1 treatment. Moreover, resolvin D1 attenuated the number of autophagic vacuoles and expressions of autophagy-related markers.. Autophagic flux is impaired in cerulein-induced AP. Resolvin D1 ameliorate the severity of mice with cerulein-induced acute pancreatitis, possible attributing to its reducing impaired autophagy and restoring autophagic flux.

Topics: Animals; Anti-Inflammatory Agents; Autophagy; Beclin-1; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Infusions, Parenteral; Macrophage Activation; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Pancreatitis, Acute Necrotizing; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Animals; Anti-Inflammatory Agents; Blood Vessel Prosthesis Implantation; Carotid Artery, Common; Cell Proliferation; Chemotaxis, Leukocyte; Disease Models, Animal; Docosahexaenoic Acids; Drug Carriers; Female; Gels; Graft Occlusion, Vascular; Hyperplasia; Jugular Veins; Neointima; Poloxamer; Polylactic Acid-Polyglycolic Acid Copolymer; Rabbits; Time Factors

Topics: Animals; Aortic Aneurysm, Abdominal; Disease Models, Animal; Docosahexaenoic Acids; Mice

Resolvins have been shown to attenuate inflammation, whereas NETosis, the process of neutrophils releasing neutrophil extracellular traps (NETs), produces increased inflammation. It is hypothesized that treatment of animals with resolvin D1 (RvD1) would reduce abdominal aortic aneurysm (AAA) formation by inhibiting NETosis.. The day 14 RvD1-treated group demonstrated 42% reduced AAA diameter compared with the elastase group (P < .001). On postoperative day 3, the RvD1-treated group showed decreased levels of NETosis markers citrullinated histone H3 (P = .04) and neutrophil elastase (P = .002) compared with the elastase group. Among important cytokines involved in AAA formation, interleukin (IL) 1β was downregulated (P = .02) whereas IL-10, a protective cytokine, was upregulated (P = .01) in the RvD1-treated group. Active matrix metalloproteinase 2 also decreased in the RvD1-treated group (P = .03). The RvD1-treated group in the Ang II AAA model, a second model, demonstrated reduced AAA diameter compared with the Ang II control group on day 28 (P < .046). The RvD1-treated group showed decreased levels of citrullinated histone H3 on day 3 (P = .002). Cytokines interferon γ, IL-1β, C-X-C motif chemokine ligand 10, monocyte chemotactic protein 1, and regulated on activation, normal T cell expressed and secreted (RANTES) were all decreased on day 28 (P < .05).. RvD1-mediated inhibition of NETosis may represent a future medical treatment for the attenuation of AAA growth.

Topics: Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Citrullination; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Extracellular Traps; Histones; Inflammation Mediators; Matrix Metalloproteinase 2; Mice, Inbred C57BL; Mice, Knockout, ApoE; Neutrophils; Pancreatic Elastase; Vascular Remodeling

Resolvin D1 and D2 are bioactive lipid mediators that are generated from docosahexaenoic acid. Although recent preclinical studies suggest that these compounds have antidepressant effects, their mechanisms of action remain unclear.. We investigated mechanisms underlying the antidepressant effects of resolvin D1 and resolvin D2 in lipopolysaccharide (0.8 mg/kg, i.p.)-induced depression model mice using a tail suspension test.. I.c.v. infusion of resolvin D1 (10 ng) and resolvin D2 (10 ng) produced antidepressant effects; these effects were significantly blocked by a resolvin D1 receptor antagonist WRW4 (10 µg, i.c.v.) and a resolvin D2 receptor antagonist O-1918 (10 µg, i.c.v.), respectively. The mammalian target of rapamycin complex 1 inhibitor rapamycin (10 mg/kg, i.p.) and a mitogen-activated protein kinase kinase inhibitor U0126 (5 µg, i.c.v.) significantly blocked the antidepressant effects of resolvin D1 and resolvin D2. An AMPA receptor antagonist NBQX (10 mg/kg, i.p.) and a phosphoinositide 3-kinase inhibitor LY294002 (3 µg, i.c.v.) blocked the antidepressant effects of resolvin D1 significantly, but not of resolvin D2. Bilateral infusions of resolvin D1 (0.3 ng/side) or resolvin D2 (0.3 ng/side) into the medial prefrontal cortex or dentate gyrus of the hippocampus produced antidepressant effects.. These findings demonstrate that resolvin D1 and resolvin D2 produce antidepressant effects via the mammalian target of rapamycin complex 1 signaling pathway, and that the medial prefrontal cortex and dentate gyrus are important brain regions for these antidepressant effects. These compounds and their receptors may be promising targets for the development of novel rapid-acting antidepressants, like ketamine and scopolamine.

Topics: Animals; Antidepressive Agents; Brain; Depression; Disease Models, Animal; Docosahexaenoic Acids; Hindlimb Suspension; Immobility Response, Tonic; Injections, Intraventricular; Lipopolysaccharides; Locomotion; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred BALB C; Oligopeptides; Signal Transduction; Statistics, Nonparametric

BACKGROUND We investigated the influence of Resolvin D1 (RvD1) on the inflammatory response in PC12 cells (a cell model of Parkinson disease, PD). MATERIAL AND METHODS 4 mmol/L 1-methyl-4-phenylpyridinium ion (Mpp+) was used in PC12 cells for an in vitro PD model. 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to explore PC12 cell viability. Western blot (WB) experiments were used to identify nuclear factor-κB (NF-κB), phosphorylated extracellular signal-regulated kinase (p-ERK)/p-Jun N-terminal kinase (JNK)/p-P38 mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 protein levels. Transcription levels of inflammatory factors, for instance, TNF-α and IL-6, were explored by real-time quantitative polymerase chain reaction (RT-QPCR). Lactic dehydrogenase (LDH) level was detected by enzyme-linked immunosorbent (ELISA). Cell apoptosis was assessed by Annexin-V Fluorescein (FITC) kit. RESULTS RvD1 dose-dependently inhibited MPP+ induced upregulation of PC12 cell apoptosis/cellular damage/TNF-α and p-P38/p-ERK/NF-κB as well as downregulation of PC12 cell viability. CONCLUSIONS We can draw the conclusion that RvD1 attenuates PD via inhibiting Mpp+-induced inflammation in PC12 cells.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Apoptosis; Disease Models, Animal; Docosahexaenoic Acids; Extracellular Signal-Regulated MAP Kinases; Flow Cytometry; Inflammation; Interleukin-6; MAP Kinase Kinase 4; MAP Kinase Signaling System; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Parkinson Disease; PC12 Cells; Phosphorylation; Rats; Tumor Necrosis Factor-alpha; Up-Regulation

Resolvin D1 (RvD1) and D2 (RvD2) are lipid mediators that are derived from docosahexaenoic acid. We recently demonstrated that intracerebroventricular (i.c.v.) infusions of RvD1 or RvD2 attenuate lipopolysaccharide-induced depression-like behaviors via mammalian target of rapamycin complex 1 signaling. However, the antidepressant effects of RvD1 and RvD2 have not been fully investigated. Here, we examined the antidepressant effects of RvD1 and RvD2 using the tail suspension test (TST) and forced swim test (FST) in murine chronic unpredictable stress (CUS) model. Male BALB/c mice (7 weeks) were subjected to 5 weeks of CUS and then received with a single i.c.v. infusion of RvD1 (10ng), RvD2 (10ng), or vehicle. In vehicle-infused mice, CUS significantly increased immobility in the TST both 2 and 24h after i.c.v. infusion, these depression-like behaviors were significantly ameliorated by RvD1 or RvD2. Similar results were obtained from the FST. Intracerebroventricular infusion of RvD1 or RvD2 did not affect locomotor activity. These results demonstrate that RvD1 and RvD2 produce rapid and sustained antidepressant effects in the CUS model.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Catheters, Indwelling; Chronic Disease; Depressive Disorder; Disease Models, Animal; Docosahexaenoic Acids; Male; Mice, Inbred BALB C; Motor Activity; Stress, Psychological; Time Factors; Uncertainty

Infants are generally highly susceptible to oral pathogens. Intestinal infection and the associated diarrhea are significant global causes of morbidity and mortality in infants. Among the enteric pathogens, enteropathogenic

Topics: Animals; Animals, Newborn; Bacterial Load; Citrobacter rodentium; Colitis; Diarrhea; Disease Models, Animal; Docosahexaenoic Acids; Enterobacteriaceae Infections; Intestines; Mice; Mice, Inbred C57BL; Recurrence

Intestinal wound healing is a new therapeutic goal for inflammatory bowel disease (IBD) as complete healing of the mucosa is the key element of clinical remission in IBD. Previous studies showed that termination of inflammation can be achieved by adding pro-resolving lipids like DHA and EPA exogenously. However, the roles of these lipids in mucosal healing have not been investigated. To recapitulate intestinal healing process, mice were received dextran sodium sulfate (DSS) for 7 days in the drinking water followed by regular tap water for 5 additional days. DSS-induced intestinal inflammation featuring body weight loss, histological tissue damage, increased cytokine production and infiltration of inflammatory cells was gradually reduced upon switching to water. To investigate whether endogenous lipids play a role in mucosal healing, the lipidomics analysis of mouse serum was performed. Reduced levels of arachidonic acid, the biosynthetic precursor of prostaglandin F (PGF)2α, 19H-PGF1α, the metabolite of prostacyclin, and 20H-PGF2α, the metabolite of PGF2α, suggest subsiding inflammation. In contrast, increased levels of an active metabolite of resolvin D1 along with decreased levels of its precursor DHA as well as decreased levels of the precursor of resolvin E, 18-hydroxy-eicosapentaenoic acid, suggest inauguration of mucosal healing by endogenous lipids. Furthermore, exogenously supplied fish oil enhanced the process even further. These results suggest the presence of mucosal healing regulated by endogenous pro-healing lipids and also indicate that the remission state of IBD could be prolonged by enhancing the levels of these lipids.

Topics: Animals; Arachidonic Acid; Colitis; Colon; Dextran Sulfate; Dinoprost; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Recovery of Function; Remission, Spontaneous; Weight Loss

Lipid mediators derived from omega-3 polyunsaturated fatty acids such as resolvin D1 (RvD1) accelerate the resolution of inflammation and have potential as vascular therapeutics. The objective of this study was to evaluate local perivascular delivery of RvD1 as a means to attenuate neointimal hyperplasia in a rat model of arterial injury.. Smooth muscle cells were harvested from rat aortas to study the effects of RvD1 on rat arterial vascular smooth muscle cell responses in vitro, with focus on inflammation, proliferation, migration, cytoskeletal changes, and cytotoxicity. The safety and efficacy of perivascular delivery of RvD1 through thin biodegradable three-layered poly(lactic-co-glycolic acid) wraps or 25% Pluronic F127 gels were studied in a rat model of carotid angioplasty. A total of 200 ng of RvD1 was loaded into each construct for perivascular delivery after injury. Morphometric and histologic analyses were performed 3 and 14 days after injury.. RvD1 attenuated rat arterial vascular smooth muscle cell inflammatory pathways, proliferation, migration, and mitogen-induced cytoskeletal changes in vitro, without evidence of cytotoxicity. RvD1-loaded wraps reduced neointimal formation after carotid angioplasty by 59% vs no-wrap controls (P = .001) and by 45% vs vehicle-wrap controls (P = .002). RvD1-loaded Pluronic gels similarly reduced neointimal formation by 49% vs no-gel controls (P = .02) and by 52% vs vehicle-gel controls (P = .02). No group was associated with infection, thrombosis, or negative vessel remodeling. Wraps were found to be easier to apply than gel constructs. Ki67 proliferation index was significantly lower in RvD1-loaded wrap-treated arteries compared with both no-wrap and vehicle-wrap controls at both 3 and 14 days after injury (65% vs no-wrap group and 70% vs vehicle-wrap group at day 3, 49% vs both control groups at day 14; P < .05). Similarly, oxidative stress (30% and 29%; P < .05) and nuclear factor κB activation (42% and 45%; P < .05) were significantly lower in the RvD1-loaded wrap group compared with both no-wrap and vehicle-wrap controls at 3 days after injury.. Local perivascular delivery of RvD1 attenuates formation of neointimal hyperplasia without associated toxicity in a rat model of carotid angioplasty. This effect is likely due to attenuation of inflammatory pathways as well as decreased arterial smooth muscle cell proliferation and migration.

Topics: Angioplasty, Balloon; Animals; Aorta; Cardiovascular Agents; Carotid Artery Diseases; Cell Movement; Cell Proliferation; Cells, Cultured; Cytoskeleton; Disease Models, Animal; Docosahexaenoic Acids; Drug Carriers; Drug Compounding; Hyperplasia; Inflammation Mediators; Ki-67 Antigen; Lactic Acid; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Oxidative Stress; Poloxamer; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats, Sprague-Dawley; Time Factors; Transcription Factor RelA

Thoracotomy results in a high frequency of chronic postoperative pain. Resolvins are endogenous molecules, synthesized and released by activated immune cells, effective against inflammatory and neuropathic pain. Different resolvins have differential actions on selective neuronal and glial receptors and enzymes. This article examines the ability of intrathecal resolvin D1 and resolvin D2 to reduce chronic post-thoracotomy pain in rats. Thoracotomy, involving intercostal incision and rib retraction, resulted in a decrease in the mechanical force threshold to induce nocifensive behavior, an enlargement of the pain-sensitive area, and an increase in the fraction of rats showing nocifensive behavior, all for at least 5 weeks. The qualitative nature of the behavioral responses to tactile stimulation changed dramatically after thoracotomy, including the appearance of vigorous behaviors, such as turning, shuddering, and squealing, all absent in naive rats. Intrathecal delivery of resolvin D1 (30 ng/30 μL), at surgery or 4 days later, halved the spread of the mechanosensitive area, lowered by 60% the percent of rats with tactile hypersensitivity, and reduced the drop in threshold for a nocifensive response, along with a reduction in the occurrence of vigorous nocifensive responses. Resolvin D2's actions on threshold changes were statistically the same. These findings suggest that intrathecal resolvins, delivered preoperatively or several days later, can prevent chronic postoperative hyperalgesia.. In studies of rats, the injection of the proresolving compounds of the resolvin-D series into spinal fluid, before or just after thoracotomy surgery, prevents the occurrence of acute and chronic pain. If these chemicals, which have shown no side-effects, were used in humans it might greatly reduce chronic postoperative pain.

Topics: Analgesics; Animals; Chronic Pain; Disease Models, Animal; Docosahexaenoic Acids; Drug Delivery Systems; Injections, Spinal; Male; Pain Measurement; Pain Threshold; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Thoracotomy; Time Factors

Vitamin A and its metabolites are known to regulate lipid metabolism. However so far, no study has assessed, whether vitamin A deficiency per se aggravates or attenuates the development of non-alcoholic fatty liver disease (NAFLD). Therefore, here, we tested the impact of vitamin A deficiency on the development of NAFLD.. Male weanling Wistar rats were fed one of the following diets; control, vitamin A-deficient (VAD), high fructose (HFr) and VAD with HFr (VADHFr) of AIN93G composition, for 16weeks, except half of the VAD diet-fed rats were shifted to HFr diet (VAD(s)HFr), at the end of 8(th) week.. Animals fed on VAD diet with HFr displayed hypotriglyceridemia (33.5mg/dL) with attenuated hepatic triglyceride accumulation (8.2mg/g), compared with HFr diet (89.5mg/dL and 20.6mg/g respectively). These changes could be partly explained by the decreased activity of glycerol 3-phosphate dehydrogenase (GPDH) and the down-regulation of stearoyl CoA desaturase 1 (SCD1), both at gene and protein levels, the key determinants of triglyceride biosynthesis. On the other hand, n-3 long chain polyunsaturated fatty acid, docosahexaenoic acid and its active metabolite; resolvin D1 (RvD1) levels were elevated in the liver and plasma of VAD diet-fed groups, which was negatively associated with triglyceride levels. All these factors confer vitamin A deficiency-mediated protection against the development of hepatic steatosis, which was also evident from the group shifted from VAD to HFr diet.. Vitamin A deficiency attenuates high fructose-induced hepatic steatosis, by regulating triglyceride synthesis, possibly through GPDH, SCD1 and RvD1.

Topics: Adiposity; Animals; Disease Models, Animal; Docosahexaenoic Acids; Down-Regulation; Fructose; Glycerolphosphate Dehydrogenase; Intra-Abdominal Fat; Liver; Male; Non-alcoholic Fatty Liver Disease; Rats, Wistar; Stearoyl-CoA Desaturase; Triglycerides; Up-Regulation; Vitamin A Deficiency; Weight Loss

Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis.

Topics: Animals; Anti-Inflammatory Agents; Ceruletide; Disease Models, Animal; Docosahexaenoic Acids; Gastrointestinal Agents; Inflammation; Interleukin-6; Lung; Lung Injury; Mice; Mice, Inbred C57BL; NF-kappa B; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Protective Agents; Signal Transduction

Accumulating evidence indicates that spinal inflammatory and immune responses play an important role in the process of radicular pain caused by intervertebral disk herniation. Resolvin D1 (RvD1) has been shown to have potent antiinflammatory and antinociceptive effects. The current study was undertaken to investigate the analgesic effect of RvD1 and its underlying mechanism in rat models of noncompressive lumbar disk herniation.. Rat models of noncompressive lumber disk herniation were established, and mechanical thresholds were evaluated using the von Frey test during an observation period of 21 days (n = 8/group). Intrathecal injection of vehicle or RvD1 (10 or 100 ng) was performed for three successive postoperative days. On day 7, the ipsilateral spinal dorsal horns and L5 dorsal root ganglions (DRGs) were removed to assess the expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-10, and transforming growth factor-β1 (TGF-β1) and the activation of nuclear factor-κB (NF-κB)/p65 and phospho-extracellular signal-regulated kinase (p-ERK) signaling (n = 30/group).. The application of nucleus pulposus to L5 DRG induced prolonged mechanical allodynia, inhibited the production of IL-10 and TGF-β1, and up-regulated the expression of TNF-α, IL-1β, NF-κB/p65, and p-ERK in the spinal dorsal horns and DRGs. Intrathecal injection of RvD1 showed a potent analgesic effect, inhibited the up-regulation of TNF-α and IL-1β, increased the release of IL-10 and TGF-β1, and attenuated the expression of NF-κB/p65 and p-ERK in a dose-dependent manner.. The current study showed that RvD1 might alleviate neuropathic pain via regulating inflammatory mediators and NF-κB/p65 and p-ERK pathways. Its antiinflammatory and proresolution properties may offer novel therapeutic approaches for the management of neuropathic pain.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Extracellular Signal-Regulated MAP Kinases; Ganglia, Spinal; Hyperalgesia; Interleukin-10; Interleukin-1beta; Intervertebral Disc Displacement; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Sciatica; Spinal Cord Dorsal Horn; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Emphysema is an irreversible disease that is characterized by destruction of lung tissue as a result of inflammation caused by smoking. Resolvin D1 (RvD1), derived from docosahexaenoic acid, is a novel lipid that resolves inflammation. The present study tested whether RvD1 prevents smoking-induced emphysema and promotes lung tissue regeneration.. C57BL/6 mice, 8 weeks of age, were randomly divided into four groups: control, RvD1 only, smoking only, and smoking with RvD1 administration. Four different protocols were used to induce emphysema and administer RvD1: mice were exposed to smoking for 4 weeks with poly(I:C) or to smoking only for 24 weeks, and RvD1 was injected within the smoking exposure period to prevent regeneration or after completion of smoking exposure to assess regeneration. The mean linear intercept and inflammation scores were measured in the lung tissue, and inflammatory cells and cytokines were measured in the bronchoalveolar lavage fluid.. Measurements of mean linear intercept showed that RvD1 significantly attenuated smoking-induced lung destruction in all emphysema models. RvD1 also reduced smoking-induced inflammatory cell infiltration, which causes the structural derangements observed in emphysema. In the 4-week prevention model, RvD1 reduced the smoking-induced increase in eosinophils and interleukin-6 in the bronchoalveolar lavage fluid. In the 24-week prevention model, RvD1 also reduced the increased neutrophils and total cell counts induced by smoking.. RvD1 attenuated smoking-induced emphysema in vivo by reducing inflammation and promoting tissue regeneration. This result suggests that RvD1 may be useful in the prevention and treatment of emphysema.

Topics: Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Docosahexaenoic Acids; Eosinophils; Female; Inflammation Mediators; Interleukin-6; Lung; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Poly I-C; Pulmonary Emphysema; Regeneration; Smoke; Smoking; Time Factors

Harnessing the actions of the resolvin pathways has the potential for the treatment of a wide range of conditions associated with overt inflammatory signalling. Aspirin-triggered resolvin D1 (AT-RvD1) has robust analgesic effects in behavioural models of pain; however, the potential underlying spinal neurophysiological mechanisms contributing to these inhibitory effects in vivo are yet to be determined. This study investigated the acute effects of spinal AT-RvD1 on evoked responses of spinal neurones in vivo in a model of acute inflammatory pain and chronic osteoarthritic (OA) pain and the relevance of alterations in spinal gene expression to these neurophysiological effects.. Pain behaviour was assessed in rats with established carrageenan-induced inflammatory or monosodium iodoacetate (MIA)-induced OA pain, and changes in spinal gene expression of resolvin receptors and relevant enzymatic pathways were examined. At timepoints of established pain behaviour, responses of deep dorsal horn wide dynamic range (WDR) neurones to transcutaneous electrical stimulation of the hind paw were recorded pre- and post direct spinal administration of AT-RvD1 (15 and 150 ng/50 μl).. AT-RvD1 (15 ng/50 μl) significantly inhibited WDR neurone responses to electrical stimuli at C- (29 % inhibition) and Aδ-fibre (27 % inhibition) intensities. Both wind-up (53 %) and post-discharge (46 %) responses of WDR neurones in carrageenan-treated animals were significantly inhibited by AT-RvD1, compared to pre-drug response (p < 0.05). These effects were abolished by spinal pre-administration of a formyl peptide receptor 2 (FPR2/ALX) antagonist, butoxy carbonyl-Phe-Leu-Phe-Leu-Phe (BOC-2) (50 μg/50 μl). AT-RvD1 did not alter evoked WDR neurone responses in non-inflamed or MIA-treated rats. Electrophysiological effects in carrageenan-inflamed rats were accompanied by a significant increase in messenger RNA (mRNA) for chemerin (ChemR23) receptor and 5-lipoxygenase-activating protein (FLAP) and a decrease in 15-lipoxygenase (15-LOX) mRNA in the ipsilateral spinal cord of the carrageenan group, compared to controls.. Our data suggest that peripheral inflammation-mediated changes in spinal FLAP expression may contribute to the novel inhibitory effects of spinal AT-RvD1 on WDR neuronal excitability, which are mediated by FPR2/ALX receptors. Inflammatory-driven changes in this pathway may offer novel targets for inflammatory pain treatment.

Topics: Action Potentials; Animals; Anti-Inflammatory Agents; Aspirin; Carrageenan; Chronic Pain; Disease Models, Animal; Docosahexaenoic Acids; Enzyme Inhibitors; Gene Expression Regulation; Inflammation; Iodoacetic Acid; Male; Nerve Fibers; Osteoarthritis; Pain Threshold; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord

Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies (AIDP), an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. EAN and AIDP are characterized by self-limitation with spontaneous recovery; however, endogenous pathways that regulate inflammation resolution in EAN and AIDP remain elusive. A pathway of endogenous mediators, especially resolvins and clearance of apoptotic cells, may be involved. Here, we determined that resolvin D1 (RvD1), its synthetic enzyme, and its receptor were greatly increased in PNS during the recovery stage of EAN. Both endogenous and exogenous RvD1 increased regulatory T (Treg) cell and anti-inflammatory macrophage counts in PNS, enhanced inflammation resolution, and promoted disease recovery in EAN rats. Moreover, RvD1 upregulated the transforming growth factor-β (TGF-β) level and pharmacologic inhibition of TGF-β signaling suppressed RvD1-induced Treg cell counts, but not anti-inflammatory macrophage counts, and RvD1-improved inflammation resolution and disease recovery in EAN rats. Mechanistically, the RvD1-enhanced macrophage phagocytosis of apoptotic T cells leading to reduced apoptotic T-cell accumulation in PNS induced TGF-β production and caused Treg cells to promote inflammation resolution and disease recovery in EAN. Therefore, these data highlight the crucial role of RvD1 as an important pro-resolving molecule in EAN and suggest its potential as a therapeutic target in human neuropathies.. Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies, an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. Here, we demonstrated that resolvin D1 (RvD1) promoted macrophage phagocytosis of apoptotic T cells in PNS, thereby upregulating transforming growth factor-β by macrophages, increased local Treg cell counts, and finally promoted inflammation resolution and disease recovery in EAN. These data highlight the crucial role of RvD1 as an important pro-resolving molecule in EAN and suggest that it has potential as a therapeutic target in human neuritis.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cells, Cultured; Disease Models, Animal; Docosahexaenoic Acids; Ectodysplasins; Enzyme Inhibitors; Forkhead Transcription Factors; Gene Expression Regulation; Macrophages; Male; Neuritis, Autoimmune, Experimental; Phagocytosis; Pteridines; Rats; Rats, Inbred Lew; Receptors, Lipoxin; Sciatic Nerve; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Del-1 is an endothelial cell-secreted anti-inflammatory protein. In humans and mice, Del-1 expression is inversely related to that of IL-17, which inhibits Del-1 through hitherto unidentified mechanism(s). Here we show that IL-17 downregulates human endothelial cell expression of Del-1 by targeting a critical transcription factor, C/EBPβ. Specifically, IL-17 causes GSK-3β-dependent phosphorylation of C/EBPβ, which is associated with diminished C/EBPβ binding to the Del-1 promoter and suppressed Del-1 expression. This inhibitory action of IL-17 can be reversed at the GSK-3β level by PI3K/Akt signalling induced by D-resolvins. The biological relevance of this regulatory network is confirmed in a mouse model of inflammatory periodontitis. Intriguingly, resolvin-D1 (RvD1) confers protection against IL-17-driven periodontal bone loss in a Del-1-dependent manner, indicating an RvD1-Del-1 axis against IL-17-induced pathological inflammation. The dissection of signalling pathways regulating Del-1 expression provides potential targets to treat inflammatory diseases associated with diminished Del-1 expression, such as periodontitis and multiple sclerosis.

Topics: Alveolar Bone Loss; Animals; Calcium-Binding Proteins; Carrier Proteins; CCAAT-Enhancer-Binding Protein-beta; Cell Adhesion Molecules; Chromatin Immunoprecipitation; Disease Models, Animal; Docosahexaenoic Acids; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Gingiva; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Human Umbilical Vein Endothelial Cells; Humans; Immunoblotting; Immunoprecipitation; Intercellular Signaling Peptides and Proteins; Interleukin-17; Mice; Mice, Knockout; Periodontitis; Peroxidase; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Signal Transduction

The wound healing process following acute inflammation after surgery is impaired in diabetes. Altered macrophage functions are linked to delayed tissue repair and pain development in diabetes. Although peroxisome proliferator-activated receptor (PPAR)-γ agonists are used to treat diabetes, their postoperative analgesic effects in diabetes have not been evaluated.. The PPARγ agonist rosiglitazone (rosi) was injected at the incision site of diabetic (db/db) mice with resolvin (Rv) D1, a lipid mediator involved in resolution of inflammation. Pain-related behavior, neutrophil infiltration, phagocytosis, and macrophage polarity were assessed for 7 days postoperatively.. Rosiglitazone and RvD1 alleviated mechanical hyperalgesia in db/db (db) mice, whereas rosiglitazone alone did not alter mechanical thresholds on days 4 (db rosi + RvD1 vs. db rosi: 0.506 ± 0.106 vs. 0.068 ± 0.12) and 7 (0.529 ± 0.184 vs. 0.153 ± 0.183) after incision (n = 10 per group). In control m/m mice, the rosiglitazone-induced analgesic effects were reversed by knockdown with arachidonate 5-lipoxygenase small interfering RNA, but these were restored by addition of RvD1. In db/db mice treated with rosiglitazone and RvD1, local infiltration of neutrophils was markedly reduced, with an associated decrease in total TdT-mediated dUTP nick-end labeling cells. Acceleration of rosiglitazone-induced phenotype conversion of infiltrated macrophages from M1 to M2 was impaired in db/db mice, but it was effectively restored by RvD1 in db/db wounds.. In diabetes, exogenous administration of RvD1 is essential for PPARγ-mediated analgesia during development of postincisional pain. Resolution of inflammation accelerated by RvD1 might promote PPARγ-mediated macrophage polarization to the M2 phenotype.

Topics: Analgesia; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Docosahexaenoic Acids; Hypoglycemic Agents; Inflammation; Macrophages; Male; Mice; Pain, Postoperative; PPAR gamma; Rosiglitazone; Thiazolidinediones

Sepsis is characterized as an uncontrolled inflammatory response. Spite et al. (Nature 461(7268):1287-1291, 2009) had demonstrated that resolvin D2, which is derived from docosahexaenoic acid (DHA), improves survival in cecal ligation and puncture (CLP)-initiated sepsis and enhances bacterial clearance without immune suppression. Resolvin D1, which is also derived from DHA and homologous with resolvin D2, is an endogenous anti-inflammatory and proresolving lipid molecule. We sought to investigate the effects of resolvin D1 on sepsis and to explore the mechanism of action. Six-to-eight-week-old male C57BL/6 mice were randomly divided into three groups: the sham group underwent the sham operation followed by tail vein injection of vehicle (0.1 % ethanol); the CLP group received vehicle (0.1 % ethanol) after CLP; the resolvin D1 group received resolvin D1 (100 ng) after CLP. Blood, peritoneal lavage fluid, and organs of mice were harvested 24 h after treatment for cytokine analysis, cell counts, bacterial cultures, histopathological studies, and apoptosis quantification. Compared with the vehicle control group, the survival rate and bacterial clearance of mice with sepsis induced by CLP were improved after resolvin D1 treatment, but the numbers of neutrophils in peritoneal lavage fluid, the inflammatory cytokines, the phosphorylation of the nuclear factor-κB (NF-κB) (P65) pathway, and the apoptosis rate of CD3(+) T lymphocytes of the thymus were suppressed. Resolvin D1 treatment improved survival in mice with sepsis induced by CLP, enhanced organism bacterial clearance, suppressed the increase of the numbers of neutrophils in peritoneal lavage fluid, reduced the release of inflammatory cytokines, and decreased the apoptosis rate of CD3(+) T lymphocytes of the thymus. These results suggest that resolvin D1 may attenuate the degree of inflammatory reaction in sepsis caused by CLP, without harming the host defense response.

Topics: Animals; Apoptosis; Bacterial Load; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Inflammation; Kaplan-Meier Estimate; Lung; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Random Allocation; Sepsis

The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biomarkers; Blood Urea Nitrogen; Claudin-4; Creatinine; Cytoprotection; Disease Models, Animal; Docosahexaenoic Acids; Endotoxins; Extracellular Signal-Regulated MAP Kinases; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Kidney; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; NF-kappa B; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Time Factors; Vascular Cell Adhesion Molecule-1

The critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that terminate the inflammatory response. We hypothesized that treatment with Resolvin D1 and/or Lipoxin A4 would prevent lung injury in a murine model of BPD.. To determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury.. C57/BL6 pups were randomized at birth to Room Air, Hyperoxia (>90% oxygen), Hyperoxia + Resolvin D1, Hyperoxia + Lipoxin A4, or Hyperoxia + Resolvin D1/Lipoxin A4. Resolvin D1 and/or Lipoxin A4 (2 ng/g) were given IP on days 0, 3, 6, and 9. On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); RT-PCR analyses of biomarkers of lung development and inflammation; and ELISA for TGFβ1 and TGFβ2.. The increased ST observed with hyperoxia exposure was normalized by both Resolvin D1 and Lipoxin A4; while, hyperoxia-induced alveolar simplification was attenuated by Lipoxin A4. Relative to hyperoxia, Resolvin D1 reduced the gene expression of CXCL2 (2.9 fold), TIMP1 (6.7 fold), and PPARγ (4.8 fold). Treatment with Lipoxin A4 also led to a reduction of CXCL2 (2.4 fold) while selectively increasing TGFβ2 (2.1 fold) and Smad3 (1.58 fold).. The histologic and biochemical changes seen in hyperoxia-induced lung injury in this murine model can be reversed by the addition of DHA and AA fatty acid downstream metabolites that terminate the inflammatory pathways and modulate growth factors. These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Docosahexaenoic Acids; Female; Hyperoxia; Lipoxins; Lung Injury; Male; Mice; Mice, Inbred C57BL; Pulmonary Alveoli

This study investigated whether the spinal or systemic treatment with the lipid resolution mediators resolvin D1 (RvD1), aspirin-triggered resolvin D1 (AT-RvD1) and resolvin D2 (RvD2) might interfere with behavioral and neurochemical changes in the mouse fibromyalgia-like model induced by reserpine. Acute administration of AT-RvD1 and RvD2 produced a significant inhibition of mechanical allodynia and thermal sensitization in reserpine-treated mice, whereas RvD1 was devoid of effects. A similar antinociceptive effect was obtained by acutely treating animals with the reference drug pregabalin. Noteworthy, the repeated administration of AT-RvD1 and RvD2 also prevented the depressive-like behavior in reserpine-treated animals, according to assessment of immobility time, although the chronic administration of pregabalin failed to affect this parameter. The induction of fibromyalgia by reserpine triggered a marked decrease of dopamine and serotonin (5-HT) levels, as examined in total brain, spinal cord, cortex and thalamus. Reserpine also elicited a reduction of glutamate levels in total brain, and a significant increase in the spinal cord and thalamus. Chronic treatment with RvD2 prevented 5-HT reduction in total brain, and reversed the glutamate increases in total brain and spinal cord. Otherwise, AT-RvD1 led to a recovery of dopamine levels in cortex, and 5-HT in thalamus, whilst it diminished brain glutamate contents. Concerning pregabalin, this drug prevented dopamine reduction in total brain, and inhibited glutamate increase in brain and spinal cord of reserpine-treated animals. Our data provide novel evidence, showing the ability of D-series resolvins AT-RvD1, and mainly RvD2, in reducing painful and depressive symptoms allied to fibromyalgia in mice.

Topics: Analgesics; Animals; Antidepressive Agents; Brain; Depression; Disease Models, Animal; Docosahexaenoic Acids; Dopamine; Fibromyalgia; gamma-Aminobutyric Acid; Glutamic Acid; Hot Temperature; Hyperalgesia; Male; Mice; Nociceptive Pain; Pregabalin; Serotonin; Spinal Cord; Touch

To study the effects of two resolvins of D series, RvD1 and 17(R)-RvD1, on inflammatory signs associated with endometriosis (ENDO).. In vivo research study.. Research laboratory.. Female Sprague-Dawley rats.. Intravenous or intraperitoneal injections of RvD1 (300 ng/kg) or 17(R)-RvD1 (300 and 900 ng/kg) in rats with surgically induced ENDO.. Vascular permeability of ectopic endometrial growths was assessed by Evans Blue extravasation; vaginal hyperalgesia was assessed with telemetered visceromotor response.. Both resolvins, but not vehicle, significantly decreased vascular permeability in ectopic endometrial tissue. 17(R)-RvD1 also significantly alleviated severity of vaginal hyperalgesia.. Our results suggest that RvD1 and 17(R)-RvD1 can be considered for further investigation of their therapeutic potential for treating ENDO.

Topics: Animals; Anti-Inflammatory Agents; Capillary Permeability; Disease Models, Animal; Docosahexaenoic Acids; Endometriosis; Female; Hyperalgesia; Injections, Intraperitoneal; Injections, Intravenous; Pain Threshold; Rats, Sprague-Dawley; Severity of Illness Index; Vagina

Resolvin D1 (RvD1), an endogenous lipid mediator derived from docosahexaenoic acid, has been reported to promote a biphasic activity in anti-inflammatory response and regulate inflammatory resolution. The present study aimed to determine the endogenous expression pattern of RvD1 in a rat model of self-resolution of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and inflammation. The ARDS model was induced by administrating LPS (2mg/kg) via tracheotomy in 138 male Sprague-Dawley rats. At specified time points, lung injury and inflammation were respectively assessed by lung histology and analysis of bronchoalveolar lavage fluid and cytokine levels. The expression of endogenous RvD1 was detected by high performance liquid chromatography and tandem mass spectrometry. The results showed that histological lung injury peaked between 6h (LPS6h) and day 3, followed by recovery over 4-10 days after LPS administration. Lung tissue polymorph nuclear cell (PMN) was significantly increased at LPS6h, and peaked between 6h to day 2. The levels of interleukin (IL)-6 and IL-10 were significantly increased at LPS6h and remained higher over day 10 as compared to baseline. Intriguingly, the endogenous RvD1 expression was decreased gradually during the first 3 days, followed by almost completely recovery over days 9-10. The finding indicated that endogenous RvD1 underwent a decrease in expression followed by gradual increase that was basically coincident with the lung injury recovery in a rat model of self-resolution LPS-induced ARDS and inflammation. Our results may help define the optimal therapeutic window for endogenous RvD1 to prevent or treat LPS-induced ARDS and inflammation.

Topics: Animals; Disease Models, Animal; Docosahexaenoic Acids; Gene Expression Regulation; Humans; Inflammation; Interleukin-10; Interleukin-6; Lipid Metabolism; Lipopolysaccharides; Lung; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Remission, Spontaneous; Respiratory Distress Syndrome

We hypothesized that inflammation induced by myocardial ischemia plays a central role in depression-like behavior after myocardial infarction (MI). Several experimental approaches that reduce inflammation also result in attenuation of depressive symptoms. We have demonstrated that Resolvin D1 (RvD1), a metabolite of omega-3 polyunsaturated fatty acids (PUFA) derived from docosahexaenoic acid, diminishes infarct size and neutrophil accumulation in the ischemic myocardium. The aim of this study is to determine if a single RvD1 injection could alleviate depressive symptoms in a rat model of MI. MI was induced in rats by occlusion of the left anterior descending coronary artery for 40 min. Five minutes before ischemia or after reperfusion, 0.1 μg of RvD1 or vehicle was injected in the left ventricle cavity. Fourteen days after MI, behavioral tests (forced swim test and socialization) were conducted to evaluate depression-like symptoms. RvD1 reduced infarct size in the treated vs. the vehicle group. Animals receiving RvD1 also showed better performance in the forced swim and social interaction tests vs. vehicle controls. These results indicate that a single RvD1 dose, given 5 min before occlusion or 5 min after the onset of reperfusion, decreases infarct size and attenuates depression-like symptoms.

Topics: Animals; Behavior, Animal; Depression; Disease Models, Animal; Docosahexaenoic Acids; Myocardial Infarction; Neutrophils; Rats; Rats, Sprague-Dawley

Resolvin D1 (RvD1) is a lipid-derived mediator generated during the resolution inflammation. While the immunoresolvent effects of Resolvins have been extensively studied in leukocytes, actions of Resolvins on intrinsic kidney cells have received little attention. The podocyte plays a central role in glomerular function, and podocyte damage can lead to proteinuria and glomerulosclerosis. This study examined whether RvD1 has renoprotective effects upon podocytes. We investigated a mouse model of adriamycin (ADR) nephropathy featuring rapid induction of podocyte damage and proteinuria followed by glomerulosclerosis. We identified a progressive loss of synaptopodin expression over a 28 day time-course of ADR nephropathy which was associated with increased acetylation of 14-3-3β and reduced synaptopodin phosphorylation. Groups of mice were given once daily RvD1 treatment (4 ng/g body weight/day) starting either 30 min (early treatment) or 14 days (late treatment) after ADR injection and continued until mice were killed on day 28. Early, but not late, RvD1 treatment attenuated ADR-induced proteinuria, glomerulosclerosis and tubulointerstitial fibrosis, modified macrophages from an M1 to M2 phenotype. Early RvD1 treatment prevented the down-regulation of synaptopodin expression and changes in 14-3-3β acetylation and synaptopodin phosphorylation. In a podocyte cell line, RvD1 was shown to prevent rapid TNF-α-induced down-regulation of synaptopodin expression. In transfection studies, TNF-α-induced a decrease in synaptopodin phosphorylation and an increase in acetylation of 14-3-3β, resulting in disassociation between 14-3-3β and synaptopodin. RvD1 prevented TNF-α induced post-translational modification of synaptopodin and 14-3-3β proteins, and maintained the synaptopodin/14-3-3β interaction. Furthermore, replacement of lysine K51, or K117+K122 in 14-3-3β with glutamine, to mimic lysine acetylation, significantly reduced the interaction between 14-3-3β and synaptopodin. In conclusion, our studies provide the first evidence that RvD1 can protect against podocyte damage by preventing down-regulation of synaptopodin through inhibition of 14-3-3β/synaptopodin dissociation. RvD1 treatment may have potential application in the treatment of chronic kidney disease.

Topics: 14-3-3 Proteins; Acetylation; Animals; Cell Line; Disease Models, Animal; Docosahexaenoic Acids; Down-Regulation; Doxorubicin; HEK293 Cells; Humans; Kidney Diseases; Kidney Glomerulus; Male; Mice; Mice, Inbred BALB C; Microfilament Proteins; Phosphorylation; Podocytes; Protein Processing, Post-Translational; Tumor Necrosis Factor-alpha

Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. Protective actions were recently uncovered for docosahexaenoic acid-derived mediators, including D-series resolvins. Here, we used a murine self-limited model of hydrochloric acid-induced ALI to determine the effects of aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) on mucosal injury. RvD1 and its receptor ALX/FPR2 were identified in murine lung after ALI. AT-RvD1 (~0.5-5 μg kg(-1)) decreased peak inflammation, including bronchoalveolar lavage fluid (BALF) neutrophils by ~75%. Animals treated with AT-RvD1 had improved epithelial and endothelial barrier integrity and decreased airway resistance concomitant with increased BALF epinephrine levels. AT-RvD1 inhibited neutrophil-platelet heterotypic interactions by downregulating both P-selectin and its ligand CD24. AT-RvD1 also significantly decreased levels of BALF pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, Kupffer cells, and tumor necrosis factor-α, and decreased nuclear factor-κB-phosphorylated p65 nuclear translocation. Taken together, these findings indicate that AT-RvD1 displays potent mucosal protection and promotes catabasis after ALI.

Topics: Acute Lung Injury; Adaptor Proteins, Signal Transducing; Airway Resistance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Blood-Air Barrier; Disease Models, Animal; Docosahexaenoic Acids; Epinephrine; Inflammation; Inflammation Mediators; Leukocytes; Macrophages, Alveolar; Male; Mice; Neutrophils; Pulmonary Edema; Receptors, Formyl Peptide; Respiratory Mucosa; Transcription Factor RelA

Asthma is a disease of airway inflammation that in most cases fails to resolve. The resolution of inflammation is an active process governed by specific chemical mediators, including D-series resolvins. In this study, we determined the impact of resolvin D1 (RvD1) and aspirin-triggered RvD1 (AT-RvD1) on the development of allergic airway responses and their resolution. Mice were allergen sensitized, and RvD1, AT-RvD1 (1, 10, or 100 ng), or vehicle was administered at select intervals before or after aerosol allergen challenge. RvD1 markedly decreased airway eosinophilia and mucus metaplasia, in part by decreasing IL-5 and IκBα degradation. For the resolution of established allergic airway responses, AT-RvD1 was even more efficacious than RvD1, leading to a marked decrease in the resolution interval for lung eosinophilia, decrements in select inflammatory peptide and lipid mediators, and more rapid resolution of airway hyperreactivity to methacholine. Relative to RvD1, AT-RvD1 resisted metabolic inactivation by macrophages, and AT-RvD1 significantly enhanced macrophage phagocytosis of IgG-OVA-coated beads in vitro and in vivo, a new proresolving mechanism for the clearance of allergen from the airways. In conclusion, RvD1 and AT-RvD1 can serve as important modulators of allergic airway responses by decreasing eosinophils and proinflammatory mediators and promoting macrophage clearance of allergen. Together, these findings identify D-series resolvins as potential proresolving therapeutic agents for allergic responses.

Topics: Animals; Aspirin; Asthma; Blotting, Western; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Gene Expression Profiling; Hypersensitivity; Immunohistochemistry; Macrophages; Male; Mice; Protein Isoforms; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction

Postoperative pain slows surgical recovery, impacting the return of normal function for weeks, months, or longer. Here we report the antihyperalgesic actions of a new compound, resolvin D1 (RvD1), known to reduce inflammation and to suppress pain after peripheral nerve injury, on the acute pain occurring after paw incision and the prolonged pain after skin-muscle retraction. Injection of RvD1 (20-40ng) into the L5-L6 intrathecal space 30minutes before surgery reduces the postincisional primary mechanical hypersensitivity, lowering the peak change by approximately 70% (with 40ng) and reducing the area under the curve (AUC) for the entire 10-day postincisional course by approximately 60%. Intrathecal injection of RvD1 on postoperative day (POD) 1 reduces the hyperalgesia to the same level as that from preoperative injection within a few hours, an effect that persists for the remaining PODs. Tactile allodynia and hyperalgesia following the skin/muscle incision retraction procedure, measured at the maximum values 12 to 14days, is totally prevented by intrathecal RvD1 (40ng) given at POD 2. However, delaying the injection until POD 9 or POD 17 results in RvD1 causing only transient and incomplete reversal of hyperalgesia, lasting for <1day. These findings demonstrate the potent, effective reduction of postoperative pain by intrathecal RvD1 given before or shortly after surgery. The much more limited effect of this compound on retraction-induced pain, when given 1 to 2weeks later, suggests that the receptors or pathways for resolvins are more important in the early than the later stages of postoperative pain. Single intrathecal injections of resolvin D1 in rats before or 1 to 2days after surgery strongly reduce postoperative pain for several weeks.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Hyperalgesia; Injections, Spinal; Male; Pain Measurement; Pain Threshold; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Skin

We recently demonstrated that ω-3-polyunsaturated fatty acids ameliorate obesity-induced adipose tissue inflammation and insulin resistance. In this study, we report novel mechanisms underlying ω-3-polyunsaturated fatty acid actions on adipose tissue, adipocytes, and stromal vascular cells (SVC). Inflamed adipose tissue from high-fat diet-induced obese mice showed increased F4/80 and CD11b double-positive macrophage staining and elevated IL-6 and MCP-1 levels. Docosahexaenoic acid (DHA; 4 μg/g) did not change the total number of macrophages but significantly reduced the percentage of high CD11b/high F4/80-expressing cells in parallel with the emergence of low-expressing CD11b/F4/80 macrophages in the adipose tissue. This effect was associated with downregulation of proinflammatory adipokines in parallel with increased expression of IL-10, CD206, arginase 1, resistin-like molecule α, and chitinase-3 like protein, indicating a phenotypic switch in macrophage polarization toward an M2-like phenotype. This shift was confined to the SVC fraction, in which secretion of Th1 cytokines (IL-6, MCP-1, and TNF-α) was blocked by DHA. Notably, resolvin D1, an anti-inflammatory and proresolving mediator biosynthesized from DHA, markedly attenuated IFN-γ/LPS-induced Th1 cytokines while upregulating arginase 1 expression in a concentration-dependent manner. Resolvin D1 also stimulated nonphlogistic phagocytosis in adipose SVC macrophages by increasing both the number of macrophages containing ingested particles and the number of phagocytosed particles and by reducing macrophage reactive oxygen species production. No changes in adipocyte area and the phosphorylation of hormone-sensitive lipase, a rate-limiting enzyme regulating adipocyte lipolysis, were observed. These findings illustrate novel mechanisms through which resolvin D1 and its precursor DHA confer anti-inflammatory and proresolving actions in inflamed adipose tissue.

Topics: Adipose Tissue; Animals; Cell Polarity; Disease Models, Animal; Docosahexaenoic Acids; Immunophenotyping; Inflammation Mediators; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Random Allocation; Signal Transduction

Resolvins and lipoxins are lipid mediators generated from essential polyunsaturated fatty acids that are the first dual anti-inflammatory and pro-resolving signals identified in the resolution phase of inflammation. Here the authors investigated the potential of aspirin-triggered lipoxin (LX) A4 analog (ATLa), resolving (Rv) D1, and RvE1, in regulating angiogenesis in a murine model.. ATLa and RvE1 receptor expression was tested in different corneal cell populations by RT-PCR. Corneal neovascularization (CNV) was induced by suture or micropellet (IL-1 beta, VEGF-A) placement. Mice were then treated with ATLa, RvD1, RvE1, or vehicle, subconjunctivally at 48-hour intervals. Infiltration of neutrophils and macrophages was quantified after immunofluorescence staining. The mRNA expression levels of inflammatory cytokines, VEGFs, and VEGFRs were analyzed by real-time PCR. CNV was evaluated intravitally and morphometrically.. The receptors for LXA4, ALX/Fpr-rs-2 and for RvE1, ChemR23 were each expressed by epithelium, stromal keratocytes, and infiltrated CD11b(+) cells in corneas. Compared to the vehicle-treated eye, ATLa-, RvD1-, and RvE1-treated eyes had reduced numbers of infiltrating neutrophils and macrophages and reduced mRNA expression levels of TNF-alpha, IL-1 alpha, IL-1 beta, VEGF-A, VEGF-C, and VEGFR2. Animals treated with these mediators had significantly suppressed suture-induced or IL-1 beta-induced hemangiogenesis (HA) but not lymphangiogenesis. Interestingly, only the application of ATLa significantly suppressed VEGF-A-induced HA.. ATLa, RvE1, and RvD1 all reduce inflammatory corneal HA by early regulation of resolution mechanisms in innate immune responses. In addition, ATLa directly inhibits VEGF-A-mediated angiogenesis and is the most potent inhibitor of NV among this new genus of dual anti-inflammatory and pro-resolving lipid mediators.

Topics: Angiogenesis Inhibitors; Animals; Corneal Neovascularization; Cytokines; Disease Models, Animal; Docosahexaenoic Acids; Down-Regulation; Eicosapentaenoic Acid; Fluorescent Antibody Technique, Indirect; Lipoxins; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophils; Receptors, Formyl Peptide; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-2