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      Anti-inflammatory role of PGD2 in acute lung inflammation and therapeutic application of its signal enhancement.

      Proceedings of the National Academy of Sciences of the United States of America
      Acute Disease, Acute Lung Injury, drug therapy, genetics, metabolism, pathology, Animals, Bone Marrow Transplantation, Endothelial Cells, Epithelial Cells, Female, Intramolecular Oxidoreductases, Lipocalins, Mice, Mice, Knockout, Neutrophil Infiltration, drug effects, Neutrophils, Pneumonia, Prostaglandin D2, Pulmonary Alveoli, Receptors, Immunologic, antagonists & inhibitors, isolation & purification, Receptors, Prostaglandin, Signal Transduction, Time Factors, Transplantation, Homologous

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          Abstract

          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.

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