L‐PGDS‐derived PGD2 attenuates acute lung injury by enhancing endothelial barrier formation

Abstract Acute lung injury (ALI) is caused by various stimuli such as acid aspiration and infection, resulting in severe clinical outcomes with high mortality. Prostaglandin D 2 (PGD 2 ) is a lipid mediator produced in the lungs of patients with ALI. There are two prostaglandin D synthases (PGDS), namely, lipocalin‐type PGDS (L‐PGDS) and hematopoietic PGDS (H‐PGDS). We previously reported the anti‐inflammatory role of H‐PGDS‐derived PGD 2 in an endotoxin‐induced murine ALI model. Therefore, in this study, we investigated the role of L‐PGDS‐derived PGD 2 in ALI in comparison to H‐PGDS‐derived PGD 2 . Intratracheal administration of HCl caused lung inflammation accompanied by tissue edema and neutrophil accumulation in mouse lungs. The deficiency of both L‐PGDS and H‐PGDS exacerbated HCl‐induced lung dysfunction to a similar extent. Furthermore, a detailed investigation revealed that L‐PGDS‐derived PGD 2 inhibited lung edema, while H‐PGDS‐derived PGD 2 inhibited neutrophil infiltration. Immunostaining showed that inflamed endothelial/epithelial cells express L‐PGDS, while macrophages and neutrophils express H‐PGDS. Hematopoietic reconstitution with WT bone marrow did not rescue the exacerbated lung edema in L‐PGDS deficient mice, indicating the importance of nonhematopoietic endothelial/epithelial cell‐expressing L‐PGDS for protection against ALI. A modified Miles assay showed that L‐PGDS deficiency accelerated vascular hyper‐permeability in the inflamed lung, which was suppressed by the stimulation of D prostanoid (DP) receptor, a PGD 2 receptor. In vitro , DP agonism enhanced the barrier function of endothelial cells but not epithelial cells. Taken together, our results suggest that in the HCl‐induced murine ALI model PGD 2 was produced locally by inflamed endothelial and epithelial L‐PGDS and this enhanced the endothelial barrier through the DP receptor. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.