Probst Clemens K, Montesi Sydney B, Medoff Benjamin D, Shea Barry S, Knipe Rachel S
Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.
Division of Pulmonary and Critical Care Medicine, Brown University and Rhode Island Hospital, Providence, RI, USA.
Eur Respir J. 2020 Jul 16;56(1). doi: 10.1183/13993003.00100-2019. Print 2020 Jul.
Idiopathic pulmonary fibrosis (IPF) is thought to result from aberrant tissue repair processes in response to chronic or repetitive lung injury. The origin and nature of the injury, as well as its cellular and molecular targets, are likely heterogeneous, which complicates accurate pre-clinical modelling of the disease and makes therapeutic targeting a challenge. Efforts are underway to identify central pathways in fibrogenesis which may allow targeting of aberrant repair processes regardless of the initial injury stimulus. Dysregulated endothelial permeability and vascular leak have long been studied for their role in acute lung injury and repair. Evidence that these processes are of importance to the pathogenesis of fibrotic lung disease is growing. Endothelial permeability is increased in non-fibrosing lung diseases, but it resolves in a self-limited fashion in conditions such as bacterial pneumonia and acute respiratory distress syndrome. In progressive fibrosing diseases such as IPF, permeability appears to persist, however, and may also predict mortality. In this hypothesis-generating review, we summarise available data on the role of endothelial permeability in IPF and focus on the deleterious consequences of sustained endothelial hyperpermeability in response to and during pulmonary inflammation and fibrosis. We propose that persistent permeability and vascular leak in the lung have the potential to establish and amplify the pro-fibrotic environment. Therapeutic interventions aimed at recognising and "plugging" the leak may therefore be of significant benefit for preventing the transition from lung injury to fibrosis and should be areas for future research.
特发性肺纤维化（IPF）被认为是慢性或重复性肺损伤后异常组织修复过程的结果。损伤的起源和性质，以及其细胞和分子靶点可能具有异质性，这使得该疾病的准确临床前建模变得复杂，并使治疗靶点成为一项挑战。目前正在努力确定纤维化形成的核心途径，这可能允许针对异常修复过程进行靶向治疗，而不管最初的损伤刺激是什么。内皮通透性失调和血管渗漏在急性肺损伤和修复中的作用长期以来一直受到研究。这些过程对纤维化肺病发病机制很重要的证据越来越多。在非纤维化肺病中内皮通透性增加，但在细菌性肺炎和急性呼吸窘迫综合征等情况下，它会以自限性方式消退。然而，在诸如IPF等进行性纤维化疾病中，通透性似乎持续存在，并且还可能预测死亡率。在这篇提出假设的综述中，我们总结了关于内皮通透性在IPF中作用的现有数据，并关注持续内皮高通透性在肺部炎症和纤维化反应期间及过程中的有害后果。我们提出，肺中持续的通透性和血管渗漏有可能建立并放大促纤维化环境。因此，旨在识别和“封堵”渗漏的治疗干预措施可能对预防从肺损伤到纤维化的转变具有显著益处，并且应该成为未来研究的领域。
