Thromboxane A2 (TXA2) is produced in the lungs of patients suffering from acute lung injury (ALI). We assessed its contribution in disease progression using three different ALI mouse models. The administration of hydrochloric acid (HCl) or oleic acid (OA)+ lipopolysaccharide (LPS) caused tissue edema and neutrophil infiltration with TXA2 production in the lungs of the experimental mice. The administration of LPS induced only neutrophil accumulation without TXA2 production. Pretreatment with T prostanoid receptor (TP) antagonist attenuated the tissue edema but not neutrophil infiltration in these models. Intravital imaging and immunostaining demonstrated that administration of TP agonist caused vascular hyper-permeability by disrupting the endothelial barrier formation in the mouse ear. In vitro experiments showed that TP-stimulation disrupted the endothelial adherens junction, and it was inhibited by Ca2+ channel blockade or Rho kinase inhibition. Thus endogenous TXA2 exacerbates ALI, and its blockade attenuates it by modulating the extent of lung edema. This can be explained by the endothelial hyper-permeability caused by the activation of TXA2-TP axis, via Ca2+- and Rho kinase-dependent signaling.

Although more than 100 lipid metabolites have been identified, their bioactivities remain unknown. In a previous study, we discovered that the production of several lipid metabolites in the intestines dramatically changed in colitis. Of these metabolites, 5,6-dihydroxyeicosatetraenoic acid (DiHETE) possesses novel anti-inflammatory activity in the vasculature. In this study, we used mouse and human umbilical vein endothelial cell (HUVEC) models to elucidate the mechanisms underlying the vascular activity of lipid metabolites, particularly those related to the release of histamine, a major proinflammatory mediator that stimulates endothelial cells to produce NO, a mediator of vascular relaxation and hyperpermeability, by activating intracellular Ca concentration-dependent signaling. In a mouse ear, the administration of 5,6-DiHETE did not induce inflammatory reactions, and pretreatment with 5,6-DiHETE inhibited histamine-induced inflammation, specifically vascular dilation and hyperpermeability. In an isolated mouse aorta, 5,6-DiHETE treatment did not influence vascular contraction but attenuated acetylcholine-induced vascular relaxation. In HUVECs, treatment with 5,6-DiHETE inhibited histamine-induced endothelial barrier disruption and inhibited the production of NO. Most notably, 5,6-DiHETE inhibited histamine-induced increases in intracellular Ca concentrations in HUVECs. Our findings suggest that 5,6-DiHETE attenuates vascular hyperpermeability during inflammation by inhibiting endothelial Ca elevation, which might lead to a novel pharmacological strategy against inflammatory diseases.

Acute lung injury (ALI) is caused by various stimuli such as acid aspiration and infection, resulting in severe clinical outcomes with high mortality. Prostaglandin D2 (PGD2) 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 PGD2 in an endotoxin‐induced murine ALI model. Therefore, in this study, we investigated the role of L‐PGDS‐derived PGD2 in ALI in comparison to H‐PGDS‐derived PGD2. 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 PGD2 inhibited lung edema, while H‐PGDS‐derived PGD2 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 PGD2 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 PGD2 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.

Atopic dermatitis (AD) is the most common inflammatory skin disease in children. The serum level of thymus and activation-regulated chemokine (TARC) is a useful AD index to reflect disease severity; however, it requires blood collection from young children. In comparison, urine samples are easier to collect in a pediatric clinical setting. Here, we analyzed the lipids excreted in urine

Lipocalin-type PG D synthase (L-PGDS) has two roles: it can be a PGD synthase, or it can be a carrier protein of hydrophobic small molecules. In this study, we investigated the dual roles of L-PGDS in acute lung injury by using L-PGDSdeficient and point-mutated mice, which lack PGD 2 producibility but maintain lipocalin ability. Hydrochloride (HCl) administration (0.1 M intratracheally for 6 h) caused hemorrhage and dysfunction in the wild-type (WT) mouse lung. These symptoms were accompanied by an increase in PGD 2 production. Both deficiency and point mutation of L-PGDS aggravated the HCl-induced hemorrhage and dysfunction. Although both the gene modifications decreased PGD 2 production, only L-PGDSdeficient mice, but not point mutation mice, lacked protein expressions of L-PGDS in the lungs. In the WT mice, HCl administration caused pulmonary edema, indexed as an increase in lung water content and protein leakage in bronchoalveolar lavage fluid. L-PGDS deficiency and point mutation similarly aggravated edema formation. HCl administration also stimulated mucin production and bronchoalveolar lavage fluid leukocyte infiltration in the WT mouse lungs. Of interest, L-PGDS deficiency, but not point mutation, exacerbated these manifestations. Consistently, only L-PGDS deficiency increased the mRNA expression of IL-33, which stimulates mucin production in the inflamed lung. These results show that L-PGDS attenuated HCl-induced acute lung injury progresses in two different ways: L-PGDS produced PGD 2 , which inhibited pulmonary edema formation, whereas its lipocalin ability decreased mucin formation and inflammatory cell infiltration in the inflamed lung.