prostaglandin-d2 and Necrosis

Duchenne muscular dystrophy is a fatal muscle wasting disease that is characterized by a deficiency in the protein dystrophin. Previously, we reported that the expression of hematopoietic prostaglandin D synthase (HPGDS) appeared in necrotic muscle fibers from patients with either Duchenne muscular dystrophy or polymyositis. HPGDS is responsible for the production of the inflammatory mediator, prostaglandin D(2). In this paper, we validated the hypothesis that HPGDS has a role in the etiology of muscular necrosis. We investigated the expression of HPGDS/ prostaglandin D(2) signaling using two different mouse models of muscle necrosis, that is, bupivacaine-induced muscle necrosis and the mdx mouse, which has a genetic muscular dystrophy. We treated each mouse model with the HPGDS-specific inhibitor, HQL-79, and measured both necrotic muscle volume and selected cytokine mRNA levels. We confirmed that HPGDS expression was induced in necrotic muscle fibers in both bupivacaine-injected muscle and mdx mice. After administration of HQL-79, necrotic muscle volume was significantly decreased in both mouse models. Additionally, mRNA levels of both CD11b and transforming growth factor beta1 were significantly lower in HQL-79-treated mdx mice than in vehicle-treated animals. We also demonstrated that HQL-79 suppressed prostaglandin D(2) production and improved muscle strength in the mdx mouse. Our results show that HPGDS augments inflammation, which is followed by muscle injury. Furthermore, the inhibition of HPGDS ameliorates muscle necrosis even in cases of genetic muscular dystrophy.

Topics: Anesthetics, Local; Animals; Blotting, Western; Bupivacaine; Cytokines; Disease Models, Animal; Humans; Intramolecular Oxidoreductases; Lipocalins; Male; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal; Muscular Dystrophy, Animal; Necrosis; Piperidines; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Brain expresses abundant lipocalin-type prostaglandin (PG) D2 (PGD2) synthase but the role of PGD2 and its metabolite, 15-deoxy-Delta(12,14) PGJ2 (15d-PGJ2) in brain protection is unclear. The aim of this study is to assess the effect of 15d-PGJ2 on neuroprotection.. Adenoviral transfer of cyclooxygenase-1 (Adv-COX-1) was used to amplify the production of 15d-PGJ2 in ischemic cortex in a rat focal infarction model. Cortical 15d-PGJ2 in Adv-COX-1-treated rats was increased by 3-fold over control, which was correlated with reduced infarct volume and activated caspase 3, and increased peroxisome proliferator activated receptor-gamma (PPARgamma) and heme oxygenase-1 (HO-1). Intraventricular infusion of 15d-PGJ2 resulted in reduction of infarct volume, which was abrogated by a PPARgamma inhibitor. Rosiglitazone infusion had a similar effect. 15d-PGJ2 and rosiglitazone at low concentrations suppressed H2O2-induced rat or human neuronal apoptosis and necrosis and induced PPARgamma and HO-1 expression. The anti-apoptotic effect was abrogated by PPARgamma inhibition.. 15d-PGJ2 suppressed ischemic brain infarction and neuronal apoptosis and necrosis in a PPARgamma dependent manner. 15d-PGJ2 may play a role in controlling acute brain damage induced by ischemia-reperfusion.

Topics: Adenoviridae; Animals; Apoptosis; Caspase 3; Caspases; Cells, Cultured; Cyclooxygenase 1; Gene Transfer Techniques; Genetic Therapy; Heme Oxygenase-1; Infarction, Middle Cerebral Artery; Male; Necrosis; Neurons; Neuroprotective Agents; PPAR gamma; Prostaglandin D2; Rats; Rats, Long-Evans; Reperfusion Injury; Rosiglitazone; Thiazolidinediones; Vasodilator Agents

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists cause cell death in several types of cancer cells. The aim of this study was to examine the effects of two PPARgamma agonists, ciglitazone and 15-deoxy-delta(12,14)-prostaglandin J2 (15dPGJ2), on the survival of thyroid carcinoma CGTH W-2 cells. Both ciglitazone and 15dPGJ2 decreased cell viability in a time- and dose-dependent manner. Cell death was mainly due to apoptosis, with a minor contribution from necrosis. Increased levels of active caspase 3, cleaved poly (ADP-ribose) polymerase (PARP), and cytosolic cytochrome-c were noted. In addition, ciglitazone and 15dPGJ2 induced detachment of CGTH W-2 cells from the culture substratum. Both the protein levels and immunostaining signals of focal adhesion (FA) proteins, including vinculin, integrin beta1, focal adhesion kinase (FAK), and paxillin were decreased after PPARgamma agonist treatment. Meanwhile, reduced phosphorylation of FAK and paxillin was noted. Furthermore, PPARgamma agonists induced expression of protein tyrosine phosphatase-PEST (PTP-PEST), and of phosphatase and tensin homologue deleted on chromosome ten (PTEN). The upregulation of these phosphatases might contribute to the dephosphorylation of FAK and paxillin, since pre-treatment with orthovanadate prevented PPARgamma agonist-induced dephosphorylation of FAK and paxillin. Perturbation of CGTH W-2 cells with anti-integrin beta1 antibodies induced FA disruption and apoptosis in the same cells, thus the downregulation of integrin beta1 by PPARgamma agonists resulted in FA disassembly and might induce apoptosis via anoikis. Our results suggested the presence of crosstalk between apoptosis and integrin-FA signaling. Moreover, upregulation and activation of PTEN was correlated with reduced phosphorylation of Akt, and this consequence disfavored cell survival. In conclusion, PPARgamma agonists induced apoptosis of thyroid carcinoma cells via the cytochrome-c caspase 3 and PTEN-Akt pathways, and induced necrosis via the PARP pathway.

Topics: Apoptosis; Asian People; Carcinoma; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Focal Adhesions; Humans; Hypoglycemic Agents; Necrosis; Neoplasm Proteins; PPAR gamma; Prostaglandin D2; Signal Transduction; Thiazolidinediones; Thyroid Neoplasms

Focal ischemia was induced in the fronto-parietal region of rat brain, by injection of Rose Bengal, followed by light activation. Focal ischemia was accompanied by formation of PGD(2) peaking 60-90 min post irradiation and declining thereafter. Increased Cycloxygenase-2 (COX-2) expression was also observed. Control ischemic rats showed distinct morphological alterations with necrosis of neurons, glial cells and blood vessels, surrounded by a halo with pyknotic cells with cytoplasm swelling and vacuolization. Compound SC58236, a selective COX-2 inhibitor, dose-dependently prevented, ischemia-induced eicosanoid formation (area under the curve (AUC) of controls: 3.11 +/- 0.87; AUC of 20 mg/kg SC58236: 0.39 +/- 0.24), and caused significant reduction of damaged area (30.7 and 18.9% at SC58236 20 and 6.6 mg/kg), suggesting that selective inhibitors of COX-2 are neuroprotective.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Fluorescent Dyes; Isoenzymes; Male; Microdialysis; Microscopy, Electron; Necrosis; Nerve Degeneration; Neurons; Neuroprotective Agents; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Wistar; Rose Bengal; Sulfonamides

The ability of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors to exacerbate inflammatory bowel disease suggests that prostaglandins are important anti-inflammatory mediators in this context. Prostaglandin D(2) has been suggested to exert anti-inflammatory effects. We investigated the possibility that prostaglandin D(2) derived from cyclooxygenase-2 plays an important role in downregulating colonic inflammation in rats. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid. At various times thereafter (from 1 h to 7 days), colonic prostaglandin synthesis and myeloperoxidase activity (index of granulocyte infiltration) were measured. Prostaglandin D(2) synthesis was elevated >4-fold above controls within 1-3 h of induction of colitis, preceding significant granulocyte infiltration. Treatment with a selective cyclooxygenase-2 inhibitor abolished the increase in prostaglandin D(2) synthesis and caused a doubling of granulocyte infiltration. Colonic granulocyte infiltration was significantly reduced by administration of prostaglandin D(2) or a DP receptor agonist (BW-245C). These results demonstrate that induction of colitis results in a rapid increase in prostaglandin D(2) synthesis via cyclooxygenase-2. Prostaglandin D(2) downregulates granulocyte infiltration into the colonic mucosa, probably through the DP receptor.

Topics: Animals; Blotting, Western; Celecoxib; Colitis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Hydantoins; Indomethacin; Intramolecular Oxidoreductases; Isoenzymes; Lipocalins; Male; Necrosis; Neutrophils; Peroxidase; Peroxisomes; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, Immunologic; Receptors, Prostaglandin; RNA, Messenger; Sulfonamides; Transcription Factors

Changes in endogenous pancreas production of prostaglandins D2, F2 alpha, E2, and E1 in early stages of acute necrotizing pancreatitis induced by intraductal administration of 3.5% sodium taurocholate have been determined by radioimmunoassay of chromatographically purified tissue extracts. For this purpose 18 male Wistar rats were randomized in three groups: control, pancreatitis, and pancreatitis plus indomethacin. Pancreas tissue samples were obtained 5 min after pancreatitis induction. In the pancreatitis-induced group, prostaglandins D2, F2 alpha, and E2 show significantly increased tissue levels relative to the controls whereas prostaglandin E1 remains unmodified. These results suggest a role for series 2 prostaglandins in the earlier stages of pancreatitis.

Topics: Acute Disease; Alprostadil; Amylases; Animals; Dinoprost; Dinoprostone; Hemorrhage; Indomethacin; Lipase; Male; Necrosis; Pancreas; Pancreatitis; Prostaglandin D2; Prostaglandins; Rats; Rats, Wistar; Taurocholic Acid