resolvin-d1 and Reperfusion-Injury

The liver is a parenchymatous organ closely related to immunity, detoxification and metabolism of the three major nutrients. The inflammatory response is a protective mechanism of the body to eliminate harmful stimuli. However, continuous inflammatory stimulation leads to occurrence of many liver diseases and brings great social burden. Resolvin D1, a member of the specialized pro-resolving lipid mediators family, exerts anti-inflammatory, anti-oxidant stress, anti-fibrosis, anti-apoptotic, and anti-tumor effects by binding to ALX/FPR2 or GPR32. RvD1 plays an important role and has great therapeutic potential in liver diseases, which has been validated in multiple models of preclinical disease. This review will provide a detailed summary of the role of RvD1 in different liver diseases, including acute liver injury, liver ischemia/reperfusion injury, non-alcoholic fatty liver disease, liver fibrosis, and liver cancer, so as to help people have a more comprehensive understanding of RvD1 and promote its further research.

Topics: Docosahexaenoic Acids; Humans; Liver Diseases; Reperfusion Injury

Dysregulation of inflammation-resolution pathways leads to postlung transplant (LTx) ischemia-reperfusion (IR) injury and allograft dysfunction. Our hypothesis is that combined treatment with specialized pro-resolving lipid mediators, that is, Resolvin D1 (RvD1) and Maresin-1 (MaR1), enhances inflammation-resolution of lung IR injury.. Bioactive proresolving lipid mediator-dependent signaling that is, RvD1/FPR2 and MaR1/LGR6- offers a novel therapeutic strategy in post-LTx injury.

Topics: Alveolar Epithelial Cells; Animals; Bronchoalveolar Lavage Fluid; Docosahexaenoic Acids; Inflammation; Lung Diseases; Lung Transplantation; Macrophages, Alveolar; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled; Reperfusion Injury; RNA, Small Interfering

Liver ischaemia and reperfusion (IR) injury is a sterile inflammatory response involving production of ROS. Mitochondrial homeostasis is maintained by mitochondrial quality control (QC). Thioredoxin (TRX) 2 is a key mitochondrial redox-sensitive protein. Resolvin D1 (RvD1), a specialized pro-resolving lipid mediator, exerts anti-inflammatory and antioxidant activities. We investigated mechanisms of RvD1 protection against IR-induced oxidative damage to the liver, focusing on TRX2-mediated mitochondrial QC.. Mice underwent partial warm IR. RvD1 was administered 1 h before ischaemia and immediately prior to reperfusion. Human liver carcinoma HepG2 cells were exposed to hypoxia/reoxygenation and transfected with TRX2 siRNA. Immunohistochemistry, Western blotting and enzyme assays were used to follow changes in mitochondrial structure and function.. RvD1 attenuated hepatocellular damage following IR, assessed by serum aminotransferase activities and histology. RvD1 reduced mitochondrial swelling, lipid peroxidation and glutamate dehydrogenase release. Impaired activities of mitochondrial complexes I and III were restored by RvD1. RvD1 enhanced expression of the mitophagy-related protein, Parkin and inhibited accumulation of PTEN-induced putative kinase 1. RvD1 restored levels of mitochondrial biogenesis proteins including PPARγ coactivator 1α, nuclear respiratory factor 1 and mitochondrial transcription factor A and mtDNA level. RvD1 attenuated the increase in levels of the mitochondrial fission-related protein, dynamin-related protein 1. IR reduced TRX2 levels while increasing TRX2 association with TRX-interacting protein. RvD1 attenuated these changes. The regulatory effects of RvD1 on mitochondrial QC were abolished by TRX2 knockdown.. We suggest that RvD1 ameliorated IR-induced hepatocellular damage by regulating TRX2-mediated mitochondrial QC.

Topics: Animals; Docosahexaenoic Acids; Hep G2 Cells; Humans; Lipid Peroxidation; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Quality Control; Reperfusion Injury; Thioredoxins

Inflammatory responses play an important role in the tissue injury during liver ischemia/reperfusion (I/R). We previously reported that resolvin D1 (RvD1) administrated prior to hepatic I/R attenuates liver injury through inhibition of inflammatory response. In this study, we investigated the effects of the aspirin-triggered resolvin D1 (AT-RvD1) on hepatic I/R and the role of miR-146b in this process.. Partial warm ischemia was performed in the left and middle hepatic lobes of Sprague-Dawley rats for 1h, followed by 6h of reperfusion. Rats received either AT-RvD1 (5μg/kg), vehicle, or AT-RvD1+miR-146b antagomir by intravenous injection 30min before ischemia. Blood and tissue samples of the rats were collected after 6-h reperfusion.. Pretreatment with AT-RvD1 significantly diminished I/R-induced elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and significantly blunted the histological injury of the liver. Moreover, AT-RvD1 significantly inhibited inflammatory response, as indicated by attenuations of TNF-α and myeloperoxidase levels. Reduced apoptosis, and increased survival rate were observed in the AT-RvD1 group compared with the control I/R group. AT-RvD1 pretreatment increased miR-146b expression in the liver of the rats with hepatic I/R. Administration of miR-146b antagomir impaired the effects of AT-RvD1 on hepatic I/R injury in rats. Downregulation of miR-146b inhibited TRAF6 and NF-κB expression in liver.. Pre-administration of AT-RvD1 attenuates hepatic I/R injury partly through modulation of miR-146b.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Apoptosis; Aspartate Aminotransferases; Aspirin; Docosahexaenoic Acids; Liver; Male; Mice; MicroRNAs; NF-kappa B; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; TNF Receptor-Associated Factor 6; Tumor Necrosis Factor-alpha

Energy metabolism disorder is a critical process in lung ischemia-reperfusion injury (LIRI). This study was aimed to determine the effects of resolvin D1 (RvD1) on the energy metabolism in LIRI.. Forty Sprague-Dawley rats were divided into the following groups: Sham group; untreated ischemia-reperfusion (IR) control; IR treated with normal saline (IR-NS); and IR treated with RvD1 (IR-RV) (100 μg/kg, iv). LIRI and energy metabolism disorder were determined in these rats.. The results revealed that the levels of interleukin (IL)-1β, tumor necrosis factor-α, IL-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, cytokine-induced neutrophil chemoattractant-1, injured alveoli rate, apoptosis index, pulmonary permeability index, malondialdehyde, ADP, and lactic acid were increased, whereas the levels of ATP, ATP/ADP, glycogen, Na(+)-K(+)-ATPase, superoxide dismutase, glutathione peroxidase activity, pulmonary surfactant associated protein-A, and oxygenation index were decreased in rats with LIRI. Except for IL-10, all these biomarkers of LIRI and its related energy metabolism disorder were significantly inhibited by RvD1 treatment. In addition, histological analysis via hematoxylin-eosin staining, and transmission electron microscopy confirmed that IR-induced structure damages of lung tissues were reduced by RvD1.. RvD1 improves the energy metabolism of LIRI disturbance, protects the mitochondrial structure and function, increases the ATP, glycogen content and Na(+)-K(+)-ATPase activity of lung tissue, balances the ratio of ATP/ADP and finally decreases the rate of apoptosis, resulting in the protection of IR-induced lung injury. The improved energy metabolism after LIRI may be related to the reduced inflammatory response, the balance of the oxidative/antioxidant and the pro-inflammatory/anti-inflammatory systems in rats.

Topics: Animals; Apoptosis; Docosahexaenoic Acids; Energy Metabolism; Inflammation; Lung; Lung Injury; Male; Oxidative Stress; Rats, Sprague-Dawley; Reperfusion Injury; Respiratory Function Tests

Lung ischemia-reperfusion injury (LIRI) is still an unsolved medical issue, which negatively affects the prognosis of many lung diseases. The aim of this study is to determine the effects of RvD1 on LIRI and the potential mechanisms involved. The results revealed that the levels of complement, immunoglobulin, cytokines, sICAM-1, MPO, MDA, CINC-1, MCP-1, ANXA-1, TLR4, NF-κBp65, apoptosis index, and pulmonary permeability index were increased, whereas the levels of SOD, GSH-PX activity, and oxygenation index were decreased in rats with LIRI. Except for ANXA-1, these responses induced by LIRI were significantly inhibited by RvD1 treatment. In addition, LIRI-induced structure damages of lung tissues were also alleviated by RvD1 as shown by H&E staining and transmission electron microscopy. The results suggest that RvD1 may play an important role in protection of LIRI via inhibition of complement, immunoglobulin, and neutrophil activation; down-regulation of TLR4/NF-κB; and the expression of a variety of inflammatory factors.

Topics: Animals; Complement System Proteins; Docosahexaenoic Acids; Down-Regulation; Immunoglobulins; Inflammation; Lung Injury; Rats; Reperfusion Injury; Toll-Like Receptor 4

Resolution of inflammation is an active process involving a novel category of lipid factors known as specialized pro-resolving lipid mediators, which includes Resolvin D1 (RvD1). While accumulating evidence suggests that RvD1 counteracts proinflammatory signaling and promotes resolution, the specific cellular targets and mechanisms of action of RvD1 remain largely unknown. In the present study, we investigated the role and molecular mechanisms of RvD1 in ischemia/reperfusion (IR)-induced sterile liver inflammation. Male C57BL/6 mice underwent 70% hepatic ischemia for 60min, followed by reperfusion. RvD1 (5, 10, and 15μg/kg, i.p.) was administered to the mice 1h before ischemia and then immediately prior to reperfusion. RvD1 attenuated IR-induced hepatocellular damage and the proinflammatory response. In purified Kupffer cells (KCs) from mice exposed to IR, the levels of M1 marker genes (Nos2a and Cd40) increased, while those of M2 marker genes (Arg1, Cd206, and Mst1r) decreased, demonstrating a proinflammatory shift. RvD1 markedly attenuated these changes. Depletion of KCs by liposome clodronate abrogated the effects of RvD1 on proinflammatory mediators and macrophage polarization. In addition, RvD1 attenuated increases in myeloperoxidase activity and Cxcl1 and Cxcl2 mRNA expression. RvD1 markedly augmented the efferocytic activity of KCs, as indicated by increases in F4/80(+)Gr-1(+) cells in the liver. However, antagonist pretreatment or gene silencing of the RvD1 receptor, ALX/FPR2, abrogated the anti-inflammatory and pro-resolving actions of RvD1. These data indicate that RvD1 ameliorates IR-induced liver injury, and this protection is associated with enhancement of M2 polarization and efferocytosis via ALX/FPR2 activation.

Topics: Adaptor Proteins, Signal Transducing; Animals; Arginase; Chemokine CXCL1; Chemokine CXCL2; Docosahexaenoic Acids; Gene Expression Regulation; Humans; Inflammation; Kupffer Cells; Lectins, C-Type; Liver; Macrophages; Male; Mannose Receptor; Mannose-Binding Lectins; Mice; Phagocytosis; Receptor Protein-Tyrosine Kinases; Receptors, Cell Surface; Receptors, Formyl Peptide; Reperfusion Injury; Signal Transduction

Resolution of inflammation is an active process driven by several new families of endogenous lipid mediators collectively coined specialized proresolving mediators (SPM). Here, we report a synthetic analog of resolvin D1 (RvD1) and aspirin-triggered RvD1, benzo-diacetylenic-17R-RvD1-methyl ester (BDA-RvD1), which was prepared using fewer steps than required for total organic synthesis of natural SPM. BDA-RvD1 was resistant to further metabolism by human recombinant 15-prostaglandin dehydrogenase, a major inactivation pathway for RvD1. In ischemia-reperfusion-initiated second organ injury, BDA-RvD1 intravenously (1 μg) reduced neutrophil infiltration into the lungs by 58 ± 9% and was significantly more potent than native RvD1. BDA-RvD1 at 100 ng/mouse also shortened the resolution interval, Ri, of Escherichia coli peritonitis with a similar potency as RvD1, by ~57%, from Ri 10.5 h to 4.5 h. With isolated human phagocytes, BDA-RvD1 at picomolar concentrations (10(-12) M) stimulated phagocytosis of zymosan A particles. BDA-RvD1 activated human recombinant G protein-coupled receptor 32/DRV1, an RvD1 receptor, in a dose-dependent manner. These results indicate that, both in vivo in mice and with isolated human cells, BDA-RvD1 shares defining proresolving actions of RvD1, including inhibiting leukocyte infiltration and stimulating phagocytosis. Moreover, they provide evidence for a new analog mimetic and example of an immunoresolvent, namely an agent that stimulates active resolution of inflammation, for a potential new therapeutic class.

Topics: Animals; Cells, Cultured; Docosahexaenoic Acids; Escherichia coli; Escherichia coli Infections; Esters; Humans; Inflammation; Lung; Macrophages; Mice; Neutrophil Infiltration; Peritonitis; Phagocytes; Phagocytosis; Receptors, G-Protein-Coupled; Reperfusion Injury; Zymosan

Inflammatory responses play an important role in the tissue damage during hepatic ischemia/reperfusion (I/R). Some resolvins have been shown to have protective properties in reducing I/R injury in the heart and kidney. The aim of the study was to investigate the effects of resolvin D1 (RvD1) on hepatic I/R.. Partial warm ischemia was produced in the left and middle hepatic lobes of Sprague-Dawley rats for 60 min, followed by 6h of reperfusion. Rats received either RvD1 (5 μg/kg) or vehicle by intravenous injection prior to ischemia. On the basis of treatment with RvD1, some rats further received the PI3K inhibitor LY294002. Blood and tissue samples from the groups were collected after 6-h reperfusion.. Our results indicate that the RvD1 receptor ALX/FPR2 is present in liver, and that pretreatment with RvD1 prior to I/R insult significantly blunted I/R-induced elevations of alanine aminotransferase (AST) and aspartate aminotransferase (ALT), and significantly improved the histological status of the liver. Moreover, RvD1 significantly inhibited inflammatory cascades, as demonstrated by attenuations of IL-6, TNF-α and myeloperoxidase levels. Reduced apoptosis, and increased phosphorylation of Akt, were observed in the RvD1 group compared with the control I/R group. These effects of RvD1 on hepatic I/R injury were diminished by the PI3K inhibitor.. Administration of RvD1 prior to hepatic I/R attenuates hepatic injury, at least in part through inhibition of inflammatory response and enhancement of phosphorylation of Akt.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Docosahexaenoic Acids; Interleukin-6; Liver; Liver Diseases; Male; Peroxidase; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, Lipoxin; Reperfusion Injury; RNA, Messenger; Tumor Necrosis Factor-alpha

Resolution of inflammation is now held to be an active process where autacoids promote homeostasis. Using functional-metabololipidomics and in vivo systems, herein we report that endogenous n-3 docosapentaenoic (DPA) acid is converted during inflammation-resolution in mice and by human leukocytes to novel n-3 products congenerous to D-series resolvins (Rv), protectins (PD) and maresins (MaR), termed specialized pro-resolving mediators (SPM). The new n-3 DPA structures include 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1(n-3 DPA)), 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1(n-3 DPA)) and related bioactive products. Each n-3 DPA-SPM displayed protective actions from second organ injury and reduced systemic inflammation in ischemia-reperfusion. The n-3 DPA-SPM, including RvD1(n-3 DPA) and MaR1(n-3 DPA), each exerted potent leukocyte directed actions in vivo. With human leukocytes each n-3 DPA-SPM reduced neutrophil chemotaxis, adhesion and enhanced macrophage phagocytosis. Together, these findings demonstrate that n-3 DPA is converted to novel immunoresolvents with actions comparable to resolvins and are likely produced in humans when n-3 DPA is elevated.

Topics: Animals; CD59 Antigens; Cell Adhesion; Cells, Cultured; Chemotaxis; Docosahexaenoic Acids; Endothelium, Vascular; Fatty Acids, Unsaturated; Humans; Inflammation; Inflammation Mediators; Leukocytes; Lipids; Macrophages; Metabolomics; Mice; Neutrophils; Peritonitis; Phagocytosis; Reperfusion Injury