Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell–(EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC-S1pr1^−/−) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC-S1pr1^−/− mice had increased and persistent vascular permeability compared with wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC-S1pr1^−/− mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM-overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.

特发性肺纤维化（IPF）是一种慢性进行性疾病，可导致呼吸衰竭导致的显着发病率和死亡率。目前批准用于临床的两种药物可以减缓肺功能下降的速度，但尚未被证明可以阻止疾病进展或逆转已形成的纤维化。因此，需要新的治疗靶点。内皮损伤和由此产生的血管通透性是对组织损伤反应的关键组成部分，并且存在于 IPF 患者中。然而，目前尚不清楚血管通透性如何影响损伤后的肺修复和纤维化。已知 1-磷酸鞘氨醇 (S1P) 等脂质介质可调节肺部的多种稳态过程，包括血管通透性。我们证明，小鼠 (EC- S1pr1 ^−/− ) 中内皮细胞 (EC) 特异性删除 S1P 受体 1 (S1PR1)会导致基线时肺血管通透性增加。在低剂量气管内博莱霉素攻击后，与野生型小鼠相比，EC- S1pr1 ^−/−小鼠的血管通透性增加且持续，这与由此产生的肺纤维化的数量和定位密切相关。EC- S1pr1 ^−/−小鼠的肺内免疫细胞浸润和凝血级联激活也有所增加。然而，ApoM 过表达小鼠中循环 S1P 配体的增加不足以预防博来霉素诱导的肺纤维化。总体而言，这些数据表明内皮细胞 S1PR1 控制肺部血管通透性，与免疫细胞浸润和血管外凝血的变化相关，并调节对肺损伤的纤维化反应。