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

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-Delta(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-Delta(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.