15-deoxy-delta(12-14)-prostaglandin-j2 and Disease-Models--Animal

Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Colitis; Dextran Sulfate; Disease Models, Animal; Immunologic Factors; Intestinal Mucosa; Macrophages; Male; Mice; Prostaglandin D2; STAT3 Transcription Factor; Treatment Outcome

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Painful conditions of the temporomandibular joint (TMJ) are challenging to manage and most attempts often result in unsatisfactory outcomes. In such context, nanocarrier systems, such as polymeric micelles, have been showing encouraging results in solving therapeutic limitations. Poloxamers are widely used, especially PL 407, because of their high biocompatibility and approval by the Food and Drug Administration (FDA) for clinical use. 15-deoxy-

Topics: Animals; Anti-Inflammatory Agents; Arthralgia; Biological Availability; Chemotaxis, Leukocyte; Cytokines; Disease Models, Animal; Drug Carriers; Drug Compounding; Formaldehyde; Inflammation Mediators; Injections, Intra-Articular; Leukocytes; Male; Micelles; Poloxamer; Prostaglandin D2; Rats, Wistar; Temporomandibular Joint; Temporomandibular Joint Disorders; Tissue Distribution

Cyclosporine A(CsA) is an immunosuppressor frequently used in the transplant surgery and in the treatment of autoimmune diseases. The therapeutic benefits of CsA are often limited by it's main side effect-nephrotoxicity. Mechanisms of chronic CsA- induced renal damage include: activation of renin-angiotensin-aldosterone system, upregulation of transforming growth factor beta (TGF-β), oxidative stress. This study was undertaken to investigate the protective effect of the peroxisome-proliferator-activated receptors gamma (PPARs-γ) agonists: rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (PGDJ2), against CsA-induced kidney injury in male Wistar rats. CsA was administered subcutaneously at a dose of 15 mg/kg/day for 28 days. Both PPAR-γ agonists were given for 28 days 0.5 hour before the administration of CsA. Rosiglitazone was administered orally at a dose of 8 mg/kg/day and PGDJ2 was given intraperitoneally at a dose of 30 μg/kg/day. CsA induced renal failure was evidenced by increased serum levels of urea, uric acid and creatinine. Serum concentrations of GSH and GSSG, lipid peroxidation products as well as NAD+/NADH, NADP+/NADPH and ADP/ATP ratios showed, that CsA induced oxidative stress and evoked an imbalanced red-ox state in the kidney. Light and electron microscope studies showed degenerative changes within renal tubules with damage to their mitochondria, interstitial fibrosis and arteriolopathy. Immunohistochemical expression of profibrotic TGF-β was assessed. The biochemical and morphological changes induced by CsA were limited by administration of both rosiglitazone and PGDJ2. Ultrastructural examination of renal tubular epithelial cells showed marked improvement within mitochondria. Our results indicate that both PPAR-γ agonists used in the experiment may play an important role in protecting against CsA-induced damage in the kidney.

Topics: Animals; Creatinine; Cyclosporine; Disease Models, Animal; Glutathione; Glutathione Disulfide; Kidney; Kidney Diseases; Male; NAD; NADP; PPAR gamma; Prostaglandin D2; Protective Agents; Rats, Wistar; Rosiglitazone; Thiazolidinediones; Urea; Uric Acid

We have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-Δ 12,14-prostaglandin J(2) (15dPGJ(2)) delays inflammation-induced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor-κB (NF-κB) by a mechanism yet to be elucidated. 15dPGJ(2) is an agonist of the second prostaglandin D(2) receptor, chemoattractant receptor homologous to the T helper 2 cell (CRTH2). In human T helper cells CRTH2 agonists induce the production of the anti-inflammatory interleukins IL-10 and IL-4. We hypothesized that CRTH2 is involved in the protective effect of 15dPGJ(2) in inflammation-induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide (LPS) was administered to CD1 mice at embryonic day 16, ± CRTH2 agonist/vehicle controls. Mice were killed at 4.5 hr to assess fetal wellbeing and to harvest myometrium and pup brain for analysis of NF-κB, and T helper type 1/2 interleukins. To examine the effects of the CRTH2 agonist on LPS-induced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH2 agonist increased fetal survival from 20 to 100% in LPS-treated mice, and inhibited circular muscle contractility ex vivo. However, it augmented LPS-induced labour and significantly increased myometrial NF-κB, IL-1β, KC-GRO, interferon-γ and tumour necrosis factor-α. This suggests that the action of 15dPGJ(2) is not via CRTH2 and therefore small molecule CRTH2 agonists are not likely to be beneficial for the prevention of inflammation-induced preterm labour.

Topics: Animals; Anti-Inflammatory Agents; Brain; Cytokines; Disease Models, Animal; Female; Fetal Death; Humans; Immunologic Factors; Inflammation; Lipopolysaccharides; Mice; Myometrium; Obstetric Labor, Premature; Peptides; Pregnancy; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin

Fetal alcohol spectrum disorders (FASD) result from ethanol exposure to the developing fetus and are the most common cause of mental retardation in the United States. These disorders are characterized by a variety of neurodevelopmental and neurodegenerative anomalies which result in significant lifetime disabilities. Thus, novel therapies are required to limit the devastating consequences of FASD. Neuropathology associated with FASD can occur throughout the central nervous system (CNS), but is particularly well characterized in the developing cerebellum. Rodent models of FASD have previously demonstrated that both Purkinje cells and granule cells, which are the two major types of neurons in the cerebellum, are highly susceptible to the toxic effects of ethanol. The current studies demonstrate that ethanol decreases the viability of cultured cerebellar granule cells and microglial cells. Interestingly, microglia have dual functionality in the CNS. They provide trophic and protective support to neurons. However, they may also become pathologically activated and produce inflammatory molecules toxic to parenchymal cells including neurons. The findings in this study demonstrate that the peroxisome proliferator-activated receptor-γ agonists 15-deoxy-Δ12,15 prostaglandin J2 and pioglitazone protect cultured granule cells and microglia from the toxic effects of ethanol. Furthermore, investigations using a newly developed mouse model of FASD and stereological cell counting methods in the cerebellum elucidate that ethanol administration to neonates is toxic to both Purkinje cell neurons as well as microglia, and that in vivo administration of PPAR-γ agonists protects these cells. In composite, these studies suggest that PPAR-γ agonists may be effective in limiting ethanol-induced toxicity to the developing CNS.

Topics: Analysis of Variance; Animals; Brain; Cell Count; Cell Survival; Cells, Cultured; Disease Models, Animal; Ethanol; Female; Fetal Alcohol Spectrum Disorders; Mice; Mice, Inbred C57BL; Microglia; Neurons; Pioglitazone; PPAR gamma; Pregnancy; Prostaglandin D2; Thiazolidinediones

Acute obstructive cholangitis is a common disease with a high mortality rate. Ligands for peroxisome proliferator-activated receptor-gamma (PPARgamma), such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (15D-PGJ(2)), have been proposed as a new class of anti-inflammatory compounds. This study investigated the effect of 15D-PGJ(2) treatment on lipopolysaccharide (LPS)-induced acute obstructive cholangitis. The rats were randomly assigned to five groups: sham operation (Sham; simple laparotomy), sham operation with intraperitoneal saline infusion (Sham+Saline), sham operation with intraperitoneal LPS infusion (Sham+LPS), bile duct ligation (BDL) with saline infusion into the bile duct (BDL+Saline), and BDL with LPS infusion into the bile duct (BDL+LPS). Biochemical assays of blood samples, histology of the liver, portal venous pressure, hyaluronic acid clearance, and expression of inflammation-associated genes in the liver were evaluated. Furthermore, the Sham+LPS and the BDL+LPS group were divided into two groups (with and without 15D-PGJ(2) treatment), and their survival rates were compared. Biochemical assays of blood samples, portal venous pressure, hyaluronic acid clearance, and expression of inflammation-associated genes in the liver were all significantly higher in the BDL+LPS group compared with those in the BDL+Saline group, indicating the presence of increased liver damage in the first group. However, preoperative administration of 15D-PGJ(2) significantly improved these outcomes. Furthermore, the survival rate after establishment of cholangitis was significantly improved by the administration of 15D-PGJ(2) in the BDL+LPS group. These results clearly demonstrate that 15D-PGJ(2) inhibits the inflammatory response and endothelial cell damage seen in acute obstructive cholangitis and could contribute to improve the outcome of this pathology.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bile Ducts; Bilirubin; Cholangitis; Cholestasis, Extrahepatic; Disease Models, Animal; Endothelium, Vascular; Gene Expression; Hyaluronic Acid; Interleukin-6; Ligation; Lipopolysaccharides; Liver; Liver Circulation; Liver Failure, Acute; Male; NF-kappa B; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; PPAR gamma; Prostaglandin D2; Rats; Rats, Wistar; Survival Analysis; Tumor Necrosis Factor-alpha

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent nuclear receptor that plays an important role in placental development and function metabolism in diabetic and control rats after midpregnancy, as well as the concentrations of the PPARgamma endogenous agonist 15deoxyDelta(12,14)Prostaglandin J(2) (15dPGJ(2)). In vitro experiments showed that 15dPGJ(2) did not regulate placental concentrations of triglycerides, cholesteryl esters, phospholipids and free fatty acids, but decreased the de novo synthesis of these lipid species. PPAR agonists were administered in vivo through dietary supplementation with either 6% olive oil or 6% safflower oil. These treatments led to increases in placental lipid mass in control tissues and more markedly in diabetic tissues. In addition, they led to reductions in the de novo lipid synthesis both in control and in diabetic placental tissues. In the placenta from diabetic rats fed with the standard diet, 15dPGJ(2) concentrations were greatly reduced. Both dietary supplementations increased the concentrations of 15dPGJ(2) in placentas from control and diabetic rats. These data indicate that, in the placenta, PPARgamma natural ligands regulate the concentration of their own endogenous ligands. In addition, they increase the placental capacity to accumulate maternal-derived lipids, and reduce the de novo lipid synthesis, thus regulating metabolic pathways that are altered in the placenta from diabetic rats and involved in the lipid transfer to the developing fetus.

Topics: Animals; Diabetes Mellitus, Experimental; Dietary Fats; Disease Models, Animal; Female; Fetal Weight; Immunoenzyme Techniques; Lipid Metabolism; Male; Placenta; PPAR gamma; Pregnancy; Prostaglandin D2; Random Allocation; Rats; Rats, Wistar

Peroxisome proliferator-activated receptor (PPAR) gamma is a member of the nuclear-receptor superfamily that binds to DNA with retinoid X receptors as PPAR-retinoid X receptor heterodimers. Recent evidence also suggests that the cyclopentenone prostaglandin 15-deoxy-DeltaPGJ2 (15d-PGJ2), which is a metabolite of the prostaglandin D2, functions as an endogenous ligand for PPAR-gamma We postulated that 15d-PGJ2 would attenuate inflammation, investigating the effects on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Furthermore, 15d-PGJ2 reduced (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) nuclear factor-kappaB activation, (4) expression of iNOS, nitrotyrosine and TNF-alpha, and (5) apoptosis (terminal deoxynucleotidyltransferase-mediated uridine triphosphate end labeling staining, Bax, Bcl-2, and FAS-L expression). In a separate set of experiments, 15d-PGJ2 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). To elucidate whether the protective effects of 15d-PGJ2 are related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, GW 9662, on the protective effects of 15d-PGJ2. GW9662 (1 mg/kg administered i.p. 30 min before treatment with 15d-PGJ2) significantly antagonized the effect of the PPAR-gamma agonist and, thus, abolished the protective effect. Taken together, our results clearly demonstrate that treatment with 15d-PGJ2 reduces the development of inflammation and tissue injury associated with spinal cord trauma.

Topics: Animals; Cyclization; Cyclopentanes; Disease Models, Animal; Inflammation Mediators; Ligands; Male; Mice; Mice, Inbred Strains; Neutrophil Infiltration; Peroxisome Proliferator-Activated Receptors; PPAR gamma; Prostaglandin D2; Random Allocation; Recovery of Function; Severity of Illness Index; Spinal Cord Injuries

PPAR-gamma has been known to induce suppression, differentiation and reversal of malignant changes in colon cancer in vitro. However, there are several reports that PPAR-gamma ligands enhance colon polyp development in APCmin mice in vivo. These contradictory results have not yet been thoroughly explained. To explain the contradictory results, we analyzed the effects of different concentrations of the PPAR-gamma agonist, 15-deoxy-D12, 14-prostaglandin (15-d Delta PGJ2) and pioglitazone, on APC gene-mutated colon cancer cell lines (HT-29). We measured cell growth and suppression by cell count and MTT assay and analyzed the expression of beta-catenin and c-Myc protein by Western blot. In addition, we inoculated HT-29 cells into APCmin mice to compare tumor size. High concentrations (10-100 microM/L 15-d Delta PGJ2 and pioglitazone) of PPAR-gamma ligand suppressed growth, while low concentrations (0.01-1 microM/L 15-d Delta PGJ2 and pioglitazone) of PPAR-gamma ligand promoted growth. In particular, the effects of 0.1 microM/L 15-d Delta PGJ2 and pioglitazone on cell growth were statistically significant (P = 0.003, P = 0.001, respectively). Tumor growth was associated with an increase in beta-catenin and c-Myc expression. The growth of xenograft tumors was greater in PPAR-gamma ligand-treated mice than in control mice (control vs day 14: P = 0.024, control vs day 28: P = 0.007). The expression of beta-catenin and c-Myc protein were also elevated in PPAR-gamma-treated mouse tissues. PPAR-gamma ligand can promote the growth of APC-mutated HT-29 colon cancer cells in vitro and in vivo. In addition, the tumor promoting effect seems to be associated with an increase in beta-catenin and c-Myc expression. We think that well-controlled clinical trials should be conducted to confirm our results and to verify clinical applications.

Topics: Animals; beta Catenin; Cell Proliferation; Colonic Neoplasms; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Genes, APC; HT29 Cells; Humans; Ligands; Mice; Mice, Nude; Mutation; Pioglitazone; PPAR gamma; Prostaglandin D2; Proto-Oncogene Proteins c-myc; Thiazolidinediones; Xenograft Model Antitumor Assays

Secondary tissue damage that occurs within days after spinal cord injury contributes significantly to permanent paralysis, sensory loss, and other functional disabilities. The acute inflammatory response is thought to contribute largely to this secondary damage. We show here that 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), a metabolite of prostaglandin D2 (PGD2) that has anti-inflammatory actions, given daily for the first 2 weeks after spinal cord contusion injury in mice, results in significant improvement of sensory and locomotor function. 15d-PGJ2-treated mice also show diminished signs of microglia/macrophage activation, increased neuronal survival, greater serotonergic innervation, and reduced demyelination in the injured spinal cord. These changes are accompanied by a reduction in chemokine and pro-inflammatory cytokine expression. Our results also indicate that 15d-PGJ2 is likely to reduce inflammation in the injured spinal cord by attenuating multiple signaling pathways: reducing activation of NF-kappa B; enhancing expression of suppressor of cytokine signaling1 and reducing the activation of Janus activated Kinase 2.

Topics: Analysis of Variance; Animals; Behavior, Animal; Cell Survival; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Female; Gene Expression Regulation; Immunologic Factors; Macrophages; Mice; Mice, Inbred BALB C; Microglia; Motor Activity; Nerve Tissue Proteins; Neurons; NF-kappa B; Prostaglandin D2; Spinal Cord Injuries; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model for multiple sclerosis (MS). We have shown earlier that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and curcumin ameliorate EAE by modulating inflammatory signaling pathways in T lymphocytes. Toll-like receptors (TLRs), expressed primarily in innate immune cells, play critical roles in the pathogenesis of EAE. T lymphocytes also express TLRs and function as costimulatory receptors to upregulate proliferation and cytokine production in response to specific agonists.. In this study, we show that naïve CD4(+) and CD8(+) T cells express detectable levels of TLR4 and TLR9 and that increase after the induction of EAE in SJL/J and C57BL/6 mice by immunization with PLPp139-151 and MOGp35-55 antigen, respectively. It is interesting to note that in vivo treatment with 15d-PGJ2 or curcumin results in a significant decrease in TLR4 and TLR9 expression in CD4(+) and CD8(+) T cells in association with the amelioration of EAE.. Although the exact mechanisms are not known, the modulation of TLR expression in T lymphocytes by 15d-PGJ(2) and curcumin suggests new therapeutic targets in the treatment of T cell-mediated autoimmune diseases.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Curcumin; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Glycoproteins; Humans; Immunization; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Prostaglandin D2; Toll-Like Receptor 4; Toll-Like Receptor 9

Stroke triggers an inflammatory cascade which contributes to a delayed cerebral damage, thus implying that antiinflammatory strategies might be useful in the treatment of acute ischaemic stroke. Since two unrelated peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, the thiazolidinedione rosiglitazone (RSG) and the cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), have been shown to possess antiinflammatory properties, we have tested their neuroprotective effects in experimental stroke. Rosiglitazone or 15d-PGJ2 were administered to rats 10 mins or 2 h after permanent middle cerebral artery occlusion (MCAO). Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected for protein expression, gene array analyses and gene shift assays. Our results show that both compounds decrease MCAO-induced infarct size and improve neurological scores. At late times, the two compounds converge in the inhibition of MCAO-induced brain expression of inducible NO synthase and the matrix metalloproteinase 9. Interestingly, at early times, complementary DNA microarrays and gene shift assays show that different mechanisms are recruited. Analysis of early nuclear p65 and late cytosolic IkappaBalpha protein levels shows that both compounds inhibit nuclear factor-kappaB signalling, although at different levels. All these results suggest both PPARgamma-dependent and independent pathways, and might be useful to design both therapeutic strategies and prognostic markers for stroke.

Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Disease Models, Animal; Drug Administration Schedule; Electrophoresis, Gel, Two-Dimensional; Gene Expression Regulation, Enzymologic; I-kappa B Proteins; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Neuroprotective Agents; NF-kappa B; NF-KappaB Inhibitor alpha; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Oligonucleotide Array Sequence Analysis; PPAR gamma; Prostaglandin D2; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Rosiglitazone; Thiazolidinediones; Time Factors

Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme involved in production of the PGD and J series, which have various role in inflammation and immunity. We evaluated the effect of treatment with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or the injection of prostaglandin D(2) synthase (PGDS) cDNA expressing-retrovirally transfected fibroblasts on bleomycin (BLM)-induced scleroderma-like skin sclerosis. Daily injection of BLM (30 microg) for 4 weeks induced histological evidence of dermal sclerosis in C3H mice. We examined the effect of injection of 15d-PGJ(2) (30 ng twice a day) or PGDS expressing-retrovirally transfected fibroblast on BLM-induced dermal sclerosis. Administration of 15d-PGJ(2) (a nonenzymatic metabolite of PGD(2)) injection of PGDS cDNA-expressing fibroblasts significantly reduced dermal sclerosis, the hydroxyproline content, and dermal thickness. Moreover, 15-d PGJ2 down-regulation of the expression of transforming growth factor beta(1) and connective tissue growth factor which had been induced by BLM. Mast cells were also increased in the skin by BLM injection and there was prominent degranulation of these mast cells along with elevated plasma histamine levels. 15-d PGJ(2) and PGDS-expressing cells also suppressed degranulation of cultured mast cells and histamine release by these cells. These results show that 15-d PGJ(2) and PGDS-expressing cells can prevent experimental skin sclerosis induced by BLM and raise the possibility of therapeutic approaches targeting of PPARgamma for the skin lesion of scleroderma.

Topics: Animals; Bleomycin; Connective Tissue Growth Factor; Disease Models, Animal; Female; Fibroblasts; Histamine Release; Hydroxyproline; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Intramolecular Oxidoreductases; Lipocalins; Mast Cells; Mice; Mice, Inbred C3H; Prostaglandin D2; RNA, Messenger; Scleroderma, Systemic; Sclerosis; Skin; Transfection

Acute lung injury (ALI) is a disease process that is characterized by diffuse inflammation in the lung parenchyma. Recent studies demonstrated that cyclooxygenase-2 (COX-2) induced at the late phase of inflammation aids in the resolution of inflammation by generating 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes.. Because 15d-PGJ2 is an endogenous electrophile, we hypothesized that it protects against ALI by activating Nrf2.. To test this hypothesis, we generated a reversible ALI model by intratracheal injection of carrageenin, an inducer of acute inflammation, whose stimulation has been known to induce COX-2.. We found that ALI induced by carrageenin was markedly exacerbated in Nrf2-knockout mice, compared with wild-type mice. Analysis of bronchoalveolar lavage fluids also revealed that the magnitude and the duration of acute inflammation, indicated by albumin concentration and the number of neutrophils, were significantly enhanced in Nrf2-knockout mice. Treatment of wild-type mice with NS-398, a selective COX-2 inhibitor, significantly exacerbated ALI to the level of Nrf2-knockout mice. In the lungs of NS-398-treated wild-type mice, both the accumulation of 15d-PGJ2 and the induction of Nrf2 target antioxidant genes were significantly attenuated. Exogenous administration of 15d-PGJ2 reversed the exacerbating effects of NS-398 with the induction of antioxidant genes.. These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.

Topics: Animals; Carrageenan; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; DNA-Binding Proteins; Macrophages; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Nitrobenzenes; Pneumonia; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Respiratory Distress Syndrome; Sulfonamides; Trans-Activators

Topics: Animals; Disease Models, Animal; Immunologic Factors; Mice; Multiple Organ Failure; Pentoxifylline; PPAR gamma; Prostaglandin D2; Vasodilator Agents; Zymosan

Fever is an important part of the host defense response, yet fever can be detrimental if it is uncontrolled. We provide the first evidence that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can attenuate the febrile response to lipopolysaccharide (LPS) in rats via an action on the brain. Furthermore, we show that PPARgamma is expressed in the hypothalamus, an important locus in the brain for fever generation. In addition, 15d-PGJ2 and its synthesizing enzyme (PGD2 synthase) were present in rat cerebrospinal fluid, and their levels were enhanced in response to systemic injection of LPS. The antipyretic effect of 15d-PGJ2 was associated with reduction in LPS-stimulated cyclooxygenase-2 expression in the hypothalamus but not in p44/p42 mitogen-activated protein kinase phosphorylation or in the expression of the PPARgamma. Thus it is likely that there is a parallel induction of an endogenous prostanoid pathway in the brain capable of limiting deleterious actions of the proinflammatory prostaglandin E2-dependent pathway.

Topics: Analgesics, Non-Narcotic; Animals; Body Temperature; Brain; Cyclooxygenase 2; Disease Models, Animal; Fever; Hypothalamus; Intramolecular Oxidoreductases; Isoenzymes; Lipocalins; Lipopolysaccharides; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Transcription Factors

15-deoxy-delta (12,14)prostaglandin J(2) (15d-PGJ(2)) has been identified as a natural ligand of the PPARgamma subtype. PPAR activation in nonadipose tissues seems to inhibit iNOS and COX2 expression. Vasoactive compounds like nitric oxide and prostaglandins are increased in pancreatic tissue from streptozotocin-diabetic rats. We hypothesize that 15d-PGJ(2) may regulate the production of these proinflammatory compounds that lead to beta cell destruction in the diabetic pathology. In this work we evaluated Ca(2+)-dependent (cNOS) and Ca(2+)-independent (iNOS) activity, nitrate/nitrite levels, 15-dPGJ(2) and prostaglandin E(2) (PGE(2)) levels in isolated pancreatic islets, and 15d-PGJ(2) levels in plasma from control and streptozotocin-diabetic rats. Our results show that cNOS is predominant in control, while iNOS isoform is increased in the diabetic islets (P < 0.01). 15d-PGJ(2) 10(-5)M inhibits cNOS and iNOS activity both in control and diabetic islets (P < 0.05). Nitrate/nitrite and PGE(2) levels are higher in diabetic than in control islets (P < 0.05 and P < 0.01, respectively). 15d-PGJ(2) 10(-5)M decreases nitrate/nitrite and PGE(2) levels both in control and in diabetic islets. Bisphenol A diglycidyl ether (BADGE), a recently described PPARgamma antagonist, seems to act as a PPARgamma agonist, diminishing nitrate/nitrite and PGE2 levels in control and diabetic islets. 15d-PGJ(2) production is lower in islets from diabetic animals compared to control (P < 0.05). Our observations suggest that 15d-PGJ(2) is able to diminish the production of vasoactive proinflammatory agents in pancreatic islets. The diminished 15d-PGJ(2) levels in the diabetic islets are probably related to the diminished capacity to limit the inflammatory response due to experimental diabetes in the rat.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Islets of Langerhans; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Prostaglandin D2; Prostaglandins E; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-gamma receptor subtype seems to play a pivotal role in the regulation of cellular proliferation and inflammation. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxyDelta(12,14)-PGJ(2) (15d-PGJ(2)), which is a metabolite of prostaglandin D(2), functions as an endogenous ligand for PPAR-gamma. We postulated that 15d-PGJ(2) would attenuate inflammation. In the present study, we have investigated the effects of 15d-PGJ(2) of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis, respectively) in animal models. We report for the first time, to our knowledge, that 15d-PGJ(2) (given at 10, 30, or 100 microg/kg i.p. in the pleurisy model or at 30 microg/kg i.p every 48 h in the arthritis model) exerts potent anti-inflammatory effects (e.g., inhibition of pleural exudate formation, mononuclear cell infiltration, delayed development of clinical indicators, and histological injury) in vivo. Furthermore, 15d-PGJ(2) reduced the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase and the expression of inducible nitric-oxide synthase and cyclooxygenase-2 in the lungs of carrageenan-treated mice and in the joints from collagen-treated mice. Thus, 15d-PGJ(2) reduces the development of acute and chronic inflammation. Therefore, the cyclopentenone prostaglandin 15d-PGJ(2) may be useful in the therapy of acute and chronic inflammation.

Topics: Animals; Arthritis, Experimental; Carrageenan; Cyclopentanes; Disease Models, Animal; Immunohistochemistry; Immunologic Factors; Inflammation; Male; Mice; Mice, Inbred BALB C; Pleurisy; Prostaglandin D2