prostaglandin-d2 and Acute-Lung-Injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin are one of the most frequently used classes of drug worldwide and inhibit prostaglandin (PG) production by inhibiting cyclooxygenase activity. Although NSAIDs are broadly used against inflammatory diseases, they have side effects including alimentary canal disorders, kidney damage, infection and cardiovascular disorders. Thus, it is necessary to elucidate the pathophysiological role of each PG in various diseases to develop better therapies with fewer and milder side effects. PGD

Topics: Acute Lung Injury; Animals; Capillary Permeability; Colitis; Dermatitis; Inflammation; Mice; Neoplasms; Neovascularization, Pathologic; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin

Lipocalin-type PG D synthase (L-PGDS) has two roles: it can be a PGD synthase, or it can be a carrier protein of hydrophobic small molecules. In this study, we investigated the dual roles of L-PGDS in acute lung injury by using L-PGDS-deficient and point-mutated mice, which lack PGD

Topics: Acute Lung Injury; Animals; Intramolecular Oxidoreductases; Lipocalins; Male; Mice; Mice, Inbred C57BL; Prostaglandin D2

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by overwhelming lung inflammation, are associated with high mortality. Cigarette smoke (CS) is one of the major causes of ALI/ARDS. Since high expression of prostaglandin (PG) D. CT‑133 (10 and 30 mg/kg), dexamethasone (1 mg/kg) and normal saline were intratracheally administrated 1 hr prior to whole-body CS-exposure for seven consecutive days to study the key characteristics of ALI. Subsequently, CSE (4%)- and PGD. CT‑133 remarkably attenuated infiltration of inflammatory cells, neutrophils, and macrophages in the BALF, albumin contents, expression of IL‑1β, IL‑6, TNF‑α and KC, lung myeloperoxidase (MPO) activity and lung histopathological alterations caused by CS exposure in mice. Moreover, CT‑133 not only reversed the uncontrolled secretion of IL‑1β, IL-6, TNF‑α and KC from CSE- and PGD. Our results provide the first evidence that targeting CRTH2 could be a new potential therapeutic option to treat CS-induced ALI.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Dexamethasone; Dose-Response Relationship, Drug; Female; Macrophages; Mice; Mice, Inbred BALB C; Neutrophils; Nicotiana; Peroxidase; Prostaglandin D2; RAW 264.7 Cells; Receptors, Immunologic; Receptors, Prostaglandin; Smoke

Acute lung injury (ALI) and acute respiratory distress syndrome are life-threatening conditions that still have no definite pharmacotherapy. Hence, we investigate the potential effectiveness and underlying mechanism of CT-133, a newly developed selective antagonist of prostaglandin D2 receptor 2 (DP2) or of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), against lipopolysaccharide (LPS)-induced ALI. CT-133 (10 or 30 mg/kg) or dexamethasone (1 mg/kg, positive control) were intragastrically administered 1 h before and 12 h after intratracheal LPS instillation, and primary neutrophils and macrophages and RAW264.7 macrophages were used to investigate the role of CT-133 in regulation of their functions. LPS induced a significant secretion of PGD

Topics: Acute Lung Injury; Animals; Boronic Acids; Bronchoalveolar Lavage Fluid; Cell Movement; Chemokines; Lipopolysaccharides; Lung; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Permeability; Prostaglandin D2; RAW 264.7 Cells; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction

A proinflammatory milieu emerging in the lung due to neutrophil accumulation and activation is a key in the pathogenesis of acute lung injury (ALI). 15-deoxy-Δ(12, 14)-prostaglandin J2 (15d-PGJ2), one of the terminal products of the cyclooxygenase-2 pathway, is known to be the endogenous ligand of peroxisome proliferator-activated receptor γ (PPAR-γ) with multiple physiological properties. Growing evidence indicates that 15d-PGJ2 has anti-inflammatory, antiproliferative, cytoprotective and pro-resolving effects. We investigated whether 15d-PGJ2 has a protective effect against endotoxin-induced acute lung injury in rats.. Twenty-four male Wistar rats were randomly assigned into four groups (n = 6 per group): sham+vehicle group, sham+15d-PGJ2 group, LPS+vehicle group, and LPS+15d-PGJ2 group. The rats were given either lipopolysaccharide (LPS, 6 mg/kg intravenously) or saline, and pretreated with 15d-PGJ2 (0.3 mg/kg intravenously) or its vehicle (dimethyl sulphoxide) 30 minutes before LPS. Histological alterations, wet/dry weight (W/D) ratio and myeloperoxidase (MPO) activity as well as tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels were determined in lung tissues four hours after LPS injection. Immunohistochemical analysis for intercellular adhesion molecule-1 (ICAM-1) expression and Western blotting analysis for nuclear factor (NF)-κB p65 translocation and IκBα protein levels were also studied.. 15d-PGJ2 pretreatment significantly attenuated LPS-induced lung injury, and reduced the increased W/D ratio, MPO activity, TNF-α, CINC-1 levels, and ICAM-1 expression in the lung. 15d-PGJ2 also suppressed the nuclear NF-κB p65 translocation and increased cytosolic IκBα levels.. 15d-PGJ2 protects against endotoxin-induced acute lung injury, most likely through the reduction of proinflammatory protein levels during endotoxemia subsequent to the inhibition of NF-κB activation.

Topics: Acute Lung Injury; Animals; Chemokine CXCL1; I-kappa B Proteins; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Prostaglandin D2; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

We investigated the role of prostaglandin D2 (PGD2) signaling in acute lung injury (ALI), focusing on its producer-effector interaction in vivo. Administration of endotoxin increased edema and neutrophil infiltration in the WT mouse lung. Gene disruption of hematopoietic PGD synthase (H-PGDS) aggravated all of the symptoms. Experiments involving bone marrow transplantation between WT and H-PGDS-deficient mice showed that PGD2 derived from alveolar nonhematopoietic lineage cells (i.e., endothelial cells and epithelial cells) promotes vascular barrier function during the early phase (day 1), whereas neutrophil-derived PGD2 attenuates its own infiltration and cytokine expression during the later phase (day 3) of ALI. Treatment with either an agonist to the PGD2 receptor, DP, or a degradation product of PGD2, 15-deoxy-Δ(12,14)-PGJ2, exerted a therapeutic action against ALI. Data obtained from bone marrow transplantation between WT and DP-deficient mice suggest that the DP signal in alveolar endothelial cells is crucial for the anti-inflammatory reactions of PGD2. In vitro, DP agonism directly enhanced endothelial barrier formation, and 15-deoxy-Δ(12,14)-PGJ2 attenuated both neutrophil migration and cytokine expression. These observations indicate that the PGD2 signaling between alveolar endothelial/epithelial cells and infiltrating neutrophils provides anti-inflammatory effects in ALI, and suggest the therapeutic potential of these signaling enhancements.

Topics: Acute Disease; Acute Lung Injury; Animals; Bone Marrow Transplantation; Endothelial Cells; Epithelial Cells; Female; Intramolecular Oxidoreductases; Lipocalins; Mice; Mice, Knockout; Neutrophil Infiltration; Neutrophils; Pneumonia; Prostaglandin D2; Pulmonary Alveoli; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction; Time Factors; Transplantation, Homologous

The NF-E2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is essential for protection against oxidative injury and inflammation including hyperoxia-induced acute lung injury. Microarray expression profiling revealed that lung peroxisome proliferator activated receptor gamma (PPARgamma) induction is suppressed in hyperoxia-susceptible Nrf2-deficient (Nrf2(-/-)) mice compared with wild-type (Nrf2(+/+)) mice. PPARgamma has pleiotropic beneficial effects including antiinflammation in multiple tissues.. We tested the hypothesis that PPARgamma is an important determinant of pulmonary responsivity to hyperoxia regulated by Nrf2.. A computational bioinformatic method was applied to screen potential AREs in the Pparg promoter for Nrf2 binding. The functional role of a potential ARE was investigated by in vitro promoter analysis. A role for PPARgamma in hyperoxia-induced acute lung injury was determined by temporal silencing of PPARgamma via intranasal delivery of PPARgamma-specific interference RNA and by administration of a PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) in mice.. Deletion or site-directed mutagenesis of a potential ARE spanning -784/-764 sequence significantly attenuated hyperoxia-increased Pparg promoter activity in airway epithelial cells overexpressing Nrf2, indicating that the -784/-764 ARE is critical for Nrf2-regulated PPARgamma expression. Mice with decreased lung PPARgamma by specific interference RNA treatment had significantly augmented hyperoxia-induced pulmonary inflammation and injury. 15 Deoxy-Delta(12,14)-prostaglandin J(2) administration significantly reduced hyperoxia-induced lung inflammation and edema in Nrf2(+/+), but not in Nrf2(-/-) mice.. Results indicate for the first time that Nrf2-driven PPARgamma induction has an essential protective role in pulmonary oxidant injury. Our observations provide new insights into the therapeutic potential of PPARgamma in airway oxidative inflammatory disorders.

Topics: Acute Lung Injury; Animals; Epithelial Cells; Gene Silencing; Immunologic Factors; Lung; Mice; NF-E2-Related Factor 2; PPAR gamma; Prostaglandin D2; RNA, Small Interfering

Topics: Acute Lung Injury; Animals; Epithelial Cells; Gene Silencing; Immunologic Factors; Lung; Mice; Mice, Knockout; NF-E2-Related Factor 2; PPAR gamma; Prostaglandin D2; RNA, Small Interfering; Up-Regulation