Journal Article

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

Nakagawa, Takayuki, Hirai, Hiroyuki, Nakamura, Masataka, Hori, Masatoshi, Ozaki, Hiroshi, Murata, Takahisa, Tsubosaka, Yoshiki, Maruyama, Toshihiko, Urade, Yoshihiro, Aritake, Kosuke, Narumiya, Shuh

2013

Overview

We investigated the role of prostaglandin D ₂ (PGD ₂) 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 PGD ₂ 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 PGD ₂ attenuates its own infiltration and cytokine expression during the later phase (day 3) of ALI. Treatment with either an agonist to the PGD ₂ receptor, DP, or a degradation product of PGD ₂, 15-deoxy-Δ ¹²,¹⁴-PGJ ₂, 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 PGD ₂. In vitro, DP agonism directly enhanced endothelial barrier formation, and 15-deoxy-Δ ¹²,¹⁴-PGJ ₂ attenuated both neutrophil migration and cytokine expression. These observations indicate that the PGD ₂ signaling between alveolar endothelial/epithelial cells and infiltrating neutrophils provides anti-inflammatory effects in ALI, and suggest the therapeutic potential of these signaling enhancements.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Acute Disease / Acute Lung Injury - drug therapy / Acute Lung Injury - genetics / Acute Lung Injury - metabolism / Acute Lung Injury - pathology / Adult respiratory distress syndrome / agonistic behavior / agonists / Animals / anti-inflammatory activity / Antiinflammatories / Biological Sciences / bone marrow transplant / Bone Marrow Transplantation / cytokines / edema / Endothelial cells / Endothelial Cells - metabolism / Endothelial Cells - pathology / endotoxins / Epithelial cells / Epithelial Cells - metabolism / Epithelial Cells - pathology / Female / gene targeting / inflammation / Intramolecular Oxidoreductases - genetics / Intramolecular Oxidoreductases - metabolism / Lipocalins - genetics / Lipocalins - metabolism / Lungs / Mice / Mice, Knockout / Neutrophil Infiltration - drug effects / Neutrophils / Neutrophils - metabolism / Neutrophils - pathology / Pneumonia - drug therapy / Pneumonia - genetics / Pneumonia - metabolism / Pneumonia - pathology / Prostaglandin D2 - genetics / Prostaglandin D2 - metabolism / prostaglandin-D synthase / Prostaglandins / Pulmonary alveoli / Pulmonary Alveoli - metabolism / Pulmonary Alveoli - pathology / Receptors / Receptors, Immunologic - antagonists & inhibitors / Receptors, Immunologic - genetics / Receptors, Immunologic - isolation & purification / Receptors, Prostaglandin - antagonists & inhibitors / Receptors, Prostaglandin - genetics / Receptors, Prostaglandin - isolation & purification / respiratory tract diseases / Signal Transduction - drug effects / Signal Transduction - genetics / Time Factors / Transplantation, Homologous