摘要

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.

译文

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致病机制，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。其病理特征是发病率和死亡率高得令人无法接受。除了保护性通气策略的成功，没有有效的药理学方法来治疗这种毁灭性的情况。理解内皮通透性调节的基本机制对于开发屏障保护治疗策略至关重要。正在进行的研究表征了特定的屏障保护机制，并确定了直接参与内皮通透性调节的细胞内靶点。越来越多的证据表明，尽管每种保护性激动剂触发了一种独特的信号通路模式，但不同的屏障保护剂可能共享选择的促进内皮屏障保护的共同机制。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。这篇文章集中于肺血管通透性的机制，回顾了参与内皮单层屏障保护的主要细胞内信号级联，并总结了最近发现的减少肺内皮屏障破坏和高通透性的化合物的最新知识。或者逆转病理损伤引起的原有肺血管屏障受损。