prostaglandin-d2 and Pleurisy

In addition to the well-recognized ability of prostaglandin D2 (PGD2) to regulate eosinophil trafficking, we asked whether PGD2 was also able to activate eosinophils and control their leukotriene C4 (LTC4)-synthesizing machinery. PGD2 administration to presensitized mice enhanced in vivo LTC4 production and formation of eosinophil lipid bodies-potential LTC4-synthesizing organelles. Immunolocalization of newly formed LTC4 demonstrated that eosinophil lipid bodies were the sites of LTC4 synthesis during PGD2-induced eosinophilic inflammation. Pretreatment with HQL-79, an inhibitor of PGD synthase, abolished LTC4 synthesis and eosinophil lipid body formation triggered by allergic challenge. Although PGD2 was able to directly activate eosinophils in vitro, in vivo PGD2-induced lipid body-driven LTC4 synthesis within eosinophils was dependent on the synergistic activity of endogenous eotaxin acting via CCR3. Our findings, that PGD2 activated eosinophils and enhanced LTC4 synthesis in vivo in addition to the established PGD2 roles in eosinophil recruitment, heighten the interest in PGD2 as a target for antiallergic therapies.

Topics: Adjuvants, Immunologic; Animals; Cells, Cultured; Chemokine CCL11; Chemokines, CC; Eosinophils; Female; Humans; Inflammation Mediators; Leukotriene C4; Lipids; Male; Mice; Pleurisy; Prostaglandin D2; Respiratory Hypersensitivity

Activated macrophages express high levels of Nrf2, a transcription factor that positively regulates the gene expression of antioxidant and detoxication enzymes. In this study, we examined how Nrf2 contributes to the anti-inflammatory process. As a model system of acute inflammation, we administered carrageenan to induce pleurisy and found that in Nrf2-deficient mice, tissue invasion by neutrophils persisted during inflammation and the recruitment of macrophages was delayed. Using an antibody against 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), it was observed that macrophages from pleural lavage accumulate 15d-PGJ(2). We show that in mouse peritoneal macrophages 15d-PGJ(2) can activate Nrf2 by forming adducts with Keap1, resulting in an Nrf2-dependent induction of heme oxygenase 1 and peroxiredoxin I (PrxI) gene expression. Administration of the cyclooxygenase 2 inhibitor NS-398 to mice with carrageenan-induced pleurisy caused persistence of neutrophil recruitment and, in macrophages, attenuated the 15d-PGJ(2) accumulation and PrxI expression. Administration of 15d-PGJ(2) into the pleural space of NS-398-treated wild-type mice largely counteracted both the decrease in PrxI and persistence of neutrophil recruitment. In contrast, these changes did not occur in the Nrf2-deficient mice. These results demonstrate that Nrf2 regulates the inflammation process downstream of 15d-PGJ(2) by orchestrating the recruitment of inflammatory cells and regulating the gene expression within those cells.

Topics: Animals; Cyclooxygenase 2; DNA-Binding Proteins; Hepatocytes; Inflammation; Isoenzymes; Macrophages; Mice; NF-E2-Related Factor 2; Peritoneum; Pleurisy; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Trans-Activators

Failure of acute inflammation to resolve leads to persistence of the inflammatory response and may contribute to the development of chronic inflammation. Thus, an understanding of inflammatory resolution will provide insight into the etiology of chronic inflammation. In an acute pleurisy, polymorphonuclear leukocytes (PMNs) were found to predominate at the onset of the lesion but decreased in number by undergoing apoptosis, the principal mechanism by which PMNs died in this model. PMNs were progressively replaced by monocytes, which differentiated into macrophages. As with PMNs, macrophages also underwent programmed cell death leading to an abatement of the inflammatory response and eventual resolution. It was found that apoptosis of both these inflammatory cell types was mediated by pro-resolving cyclooxygenase 2-derived 15deoxyDelta12-14PGJ2, which is uniquely expressed during active resolution. Although PMN programmed cell death is well understood, the observation that macrophages apoptose during resolution of acute inflammation is less well described. These results provide insight into the mechanisms that switch off acute inflammation and prevent complications of wound healing and potentially the development of immune-mediated chronic inflammation.

Topics: Acute Disease; Animals; Apoptosis; Cyclooxygenase 2; Inflammation; Isoenzymes; Leukocyte Count; Macrophages; Models, Immunological; Neutrophils; Pleurisy; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Rats

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

In this study, using rat carrageenin-induced pleurisy, we found that treatment of rats with either indomethacin or NS-398 suppressed the pleurisy at 2 h but significantly exacerbated this reaction at 48 h. Exacerbated inflammation was associated with reduced prostaglandin D(2) levels, decreased heat shock factor 1 (HSF1) activation, reduced hsp72 expression and increased activation of nuclear factor kappaB (NF-kappaB). Replacement of cyclopentenone prostaglandins by treating rats with either prostaglandin J(2) or prostaglandin D(2) reversed the exacerbating effects of cyclooxygenase inhibitors leading to the resolution of the reaction. In conclusion, we demonstrate that cyclopentenone prostaglandins may act as anti-inflammatory mediators by inducing in inflammatory cells HSF1-dependent hsp72 expression and NF-kappaB inhibition, two crucial events for the remission of inflammation.

Topics: Active Transport, Cell Nucleus; Animals; Carrageenan; Cyclooxygenase Inhibitors; Disease Models, Animal; DNA-Binding Proteins; Drug Combinations; Exudates and Transudates; Heat Shock Transcription Factors; Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Humans; Indomethacin; Male; NF-kappa B; NF-kappa B p50 Subunit; Nitrobenzenes; Pleura; Pleurisy; Prostaglandin D2; Prostaglandins; Rats; Rats, Wistar; Sulfonamides; Transcription Factor RelA; Transcription Factors

Rat pleurisy was induced by intrapleural injection of phorbol myristate acetate (PMA), a known tumor promotor and a component of croton oil. Pleural fluids at 30 min and 1 hr after PMA-injection were collected and arachidonic acid metabolites in the fluids were measured by RIA or bioassay after fractionation through reversed phase HPLC using an ODS column. The major metabolites found in the pleural fluid were 6-keto-PGF1 alpha, TXB2 and PGD2, with a small amount of PGE2. Pretreatment with 10 mg/kg indomethacin suppressed the pleural fluid accumulation and also reduced the amount of the above metabolites to the basal levels. Treatment with OKY-046, a novel thromboxane synthetase inhibitor, reduced the level of TXB2 completely, but had no effect on those of 6-keto-PGF1 alpha and PGD2, and it had no effect on pleural fluid accumulation either. The results may indicate that PGI2 plays a role for the vascular permeability increase in the early phase of pleurisy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Inflammation; Male; Platelet Aggregation; Pleurisy; Prostaglandin D2; Prostaglandins D; Radioimmunoassay; Rats; Rats, Inbred Strains; Tetradecanoylphorbol Acetate; Thromboxane B2