prostaglandin-d2 and Respiratory-Distress-Syndrome

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 subfamily comprises three members: PPAR-alpha, PPAR-beta and PPAR-gamma. PPARs have recently been implicated as regulators of cellular proliferation and inflammatory responses. Furthermore, it has been demonstrated that PPAR-gamma and PPAR-alpha reduce lung injury associated with inflammation and shock.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Humans; Ligands; PPAR alpha; PPAR gamma; Prostaglandin D2; Respiratory Distress Syndrome; Rosiglitazone; Thiazolidinediones

Prostanoids with various physiological effects in the lung, have been shown to be one of the important factors in acute lung injury. However, in large scale clinical studies, beneficial effects of NSAIDs or PGE1 have not been demonstrated. On the other hand, with progress of basic research in prostaglandin metabolic pathway, receptor and synthase of each prostanoid have been clarified, and selective COX-2 blockers have been developed and are now available in Japan. We reviewed the relationship between prostanoids, acute lung injury and the effects of COX-2 selective blockers, and discussed the present status and future perspective in this field.

Topics: Alprostadil; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Isoenzymes; Membrane Proteins; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Receptors, Cytoplasmic and Nuclear; Respiratory Distress Syndrome; Transcription Factors

Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor-homologous molecule expressed on T(H)2 cells) in regulating macrophages have not been elucidated to date.. We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo.. In vitro studies, including migration, Ca(2+) flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice.. Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca(2+) flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis.. For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation.

Topics: Animals; Calcium Signaling; Chemotaxis, Leukocyte; Cytokines; Endotoxins; Gene Expression; Humans; Inflammation Mediators; Lung; Lung Injury; Macrophages; Mice; Neutrophil Infiltration; Neutrophils; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Early detection and prevention is an important goal in acute respiratory distress syndrome research. We determined the concentration of the anti-inflammatory 15-deoxy-Δ(12,14)-prostaglandin-J2 (15d-PGJ2) and other components of the cyclopentenone prostaglandin cascade in relation to lung inflammation in cytokine (IL-1/LPS)-insufflated rats. We found that 15d-PGJ2 levels increase in the bronchoalveolar lavage (BAL) fluid of rats insufflated with cytokines 2 h before. BAL 15d-PGJ2 increases preceded neutrophil recruitment, lung injury, and oxidative stress in the lungs of cytokine-insufflated rats. 15d-PGJ2 was localized in alveolar macrophages that decreased following cytokine insufflation. 15d-PGJ2 may constitute an early biomarker of lung inflammation and may reflect an endogenous attempt to regulate ongoing inflammation in macrophages and elsewhere after cytokine insufflation.

Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Cell Count; Cytokines; Inflammation; Insufflation; L-Lactate Dehydrogenase; Lipopolysaccharides; Lung; Macrophages, Alveolar; Neutrophil Infiltration; Oxidative Stress; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome

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

15-Deoxy-delta(12,14)-prostaglandin J(2) (15d-prostaglandin J(2)) has received attention for its anti-inflammatory properties. The present study investigated the efficacy of 15d-prostaglandin J(2) on acute lung injury induced by lipopolysaccharide in mice. ICR mice were administered with 15d-prostaglandin J(2) (10 microg/kg, 100 microg/kg, or 1 mg/kg) before intratracheal challenge with lipopolysaccharide (125 microg/kg). Treatment with 15d-prostaglandin J(2) did not ameliorate rather enhanced at a dose of 1 mg/kg the neutrophilic lung inflammation and pulmonary edema by lipopolysaccharide. The enhancement was concomitant with the increased lung expression of interleukin-1 beta, macrophage inflammatory protein-1 alpha, and macrophage chemoattractant protein-1. 15d-prostaglandin J(2) increased the nuclear protein expression of peroxisome proliferator-activated receptor (PPAR)-gamma and inhibited the nuclear localization of nuclear factor-kappa B related to lipopolysaccharide. 15d-prostaglandin J(2) increased the phosphorylation of c-Jun in the presence or absence of lipopolysaccharide. Our data suggest that 15d-prostaglandin J(2) may not be useful but potentially harmful for the therapeutic option of acute lung injury.

Topics: Animals; Drug Synergism; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Prostaglandin D2; Respiratory Distress Syndrome