抄録
Acute lung injury (ALI) is caused by various stimulates including aspiration of gastric contents. Although its mortality rate is high, there is no effective treatment against ALI. Prostaglandin D2 (PGD2) is a bioactive substance which produced by lipocalin-type PGD synthase (L-PGDS) and hematopoietic PGD synthase (H-PGDS). The production of PGD2 is increased in the lung of the patients with ALI. However, its role remain unclear. Here we investigate the role of L/H-PGDS-derived PGD2 in progression of HCl-induced murine ALI model.
Intratracheal injection of HCl caused respiratory dysfunction, lung hemorrhage, neutrophil accumulation, and edema in the wild type (WT) mice. Gene deficiency of H-PGDS or L-PGDS aggravated the respiratory dysfunction and hemorrhage. H-PGDS deficiency promoted neutrophil accumulation accompanied by approximately 90% decrease of PGD2 content. On the other hand, L-PGDS deficiency strongly promoted edema formation even though the PGD2 production decreased by approximately 10%. Immuno-histological analysis showed that infiltrated macrophage expressed H-PGDS, while pulmonary endothelial/epithelial cells express L-PGDS. L-PGDS deficiency accelerated vascular hyper-permeability in HCl-treated lung compared to that in WT. The agonism of D prostanoid receptor (DP) almost completely inhibited HCl-induced hyper-permeability in both lines of mice. Consistently, DP activation enhanced barrier formation of endothelial cell, but not epithelial cell. These observations suggest that endothelial/epithelial L-PGDS locally produces PGD2 and attenuates HCl-induced ALI appearance as well as H-PGDS signaling, which caused by protecting endothelial barrier formation via DP receptor.
