Lung Injury Center, Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Compr Physiol. 2013 Jan;3(1):429-84. doi: 10.1002/cphy.c100066.
Increased endothelial permeability and reduction of alveolar liquid clearance capacity are two leading pathogenic mechanisms of pulmonary edema, which is a major complication of acute lung injury, severe pneumonia, and acute respiratory distress syndrome, the pathologies characterized by unacceptably high rates of morbidity and mortality. Besides the success in protective ventilation strategies, no efficient pharmacological approaches exist to treat this devastating condition. Understanding of fundamental mechanisms involved in regulation of endothelial permeability is essential for development of barrier protective therapeutic strategies. Ongoing studies characterized specific barrier protective mechanisms and identified intracellular targets directly involved in regulation of endothelial permeability. Growing evidence suggests that, although each protective agonist triggers a unique pattern of signaling pathways, selected common mechanisms contributing to endothelial barrier protection may be shared by different barrier protective agents. Therefore, understanding of basic barrier protective mechanisms in pulmonary endothelium is essential for selection of optimal treatment of pulmonary edema of different etiology. This article focuses on mechanisms of lung vascular permeability, reviews major intracellular signaling cascades involved in endothelial monolayer barrier preservation and summarizes a current knowledge regarding recently identified compounds which either reduce pulmonary endothelial barrier disruption and hyperpermeability, or reverse preexisting lung vascular barrier compromise induced by pathologic insults.
血管内皮通透性增加和肺泡液体清除能力降低是肺水肿的两个主要发病机制，肺水肿是急性肺损伤、严重肺炎和急性呼吸窘迫综合征的主要并发症，这些病理具有不可接受的高发病率和死亡率。除了在保护性通气策略方面取得成功外，目前尚无有效的药物治疗方法来治疗这种破坏性疾病。了解调节血管内皮通透性的基本机制对于开发屏障保护治疗策略至关重要。正在进行的研究描述了特定的屏障保护机制，并确定了直接参与调节内皮通透性的细胞内靶点。越来越多的证据表明，尽管每种保护激动剂都会引发独特的信号通路模式，但不同屏障保护剂可能具有共同的参与内皮屏障保护的常见机制。因此，了解肺内皮的基本屏障保护机制对于选择不同病因肺水肿的最佳治疗方法至关重要。本文重点介绍肺血管通透性的机制，回顾参与内皮单层屏障保护的主要细胞内信号级联，并总结关于最近发现的化合物的现有知识，这些化合物要么减少肺内皮屏障的破坏和通透性增加，要么逆转由病理损伤引起的预先存在的肺血管屏障损伤。
