First Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis 68100, Greece.
J Immunol. 2011 Jun 1;186(11):6568-75. doi: 10.4049/jimmunol.1003756. Epub 2011 Apr 29.
Neonatal respiratory distress syndrome can progress to bronchopulmonary dysplasia (BPD), a serious pulmonary fibrotic disorder. Given the involvement of the extrinsic coagulation cascade in animal models of lung fibrosis, we examined its role in BPD. We observed a higher number of neutrophils expressing tissue factor (TF) in bronchoalveolar lavage fluid (BALF) from infants with BPD than from those with uncomplicated respiratory distress syndrome together with a parallel decrease in TF and connective tissue growth factor (CTGF) in BALF supernatants during the disease course. The involvement of coagulation in the fibrotic process associated with BPD was further evaluated by treating primary human colonic myofibroblasts with BALF supernatants from infants with BPD. These human colonic myofibroblasts demonstrated an enhanced C5a- and thrombin-dependent migration. Moreover, they expressed TF in an endothelin-1-dependent manner, with subsequent activation of the extrinsic coagulation cascade and CTGF production mediated by protease-activator receptor-1 signaling. These data provide a novel mechanism for the development of BPD and indicate that endothelin-1 signaling contributes to fibrosis by upregulating a TF/thrombin amplification loop responsible for CTGF production, and offer novel and specific therapeutic targets for pulmonary fibrotic disease.
新生儿呼吸窘迫综合征可发展为支气管肺发育不良（BPD），这是一种严重的肺纤维化疾病。鉴于外源性凝血级联反应在肺纤维化动物模型中的参与，我们研究了其在 BPD 中的作用。我们观察到，与单纯呼吸窘迫综合征婴儿相比，BPD 婴儿支气管肺泡灌洗液（BALF）中表达组织因子（TF）的中性粒细胞数量更多，同时 TF 和结缔组织生长因子（CTGF）在疾病过程中BALF 上清液中的含量平行下降。通过用 BPD 婴儿的 BALF 上清液处理原代人结肠肌成纤维细胞，进一步评估了凝血在与 BPD 相关的纤维化过程中的作用。这些人结肠肌成纤维细胞表现出增强的 C5a 和凝血酶依赖性迁移。此外，它们以内皮素-1 依赖性方式表达 TF，随后通过蛋白酶激活受体-1 信号转导激活外源性凝血级联反应和 CTGF 产生。这些数据为 BPD 的发展提供了一种新的机制，并表明内皮素-1 信号通过上调负责 CTGF 产生的 TF/凝血酶放大环，促进纤维化，为肺纤维化疾病提供了新的和特定的治疗靶点。
