Increased vascular permeability is a cardinal feature of acute lung injury and restoration of the disrupted endothelial barrier function is a requisite to stem the fluid and inflammatory cells in the alveolar space. Maintenance of endothelial cell (EC) integrity is a critical determinant of vascular permeability and inflammatory responses in a variety of pulmonary disorders including sepsis, ventilator-induced lung injury, and bacterial and viral infections. Although it is well established that disruption of EC tight and adherens junctions causes increased permeability, alveolar flooding, and pulmonary edema, there is compelling evidence to support that ECs have the inherent ability to anneal the junctions and restore the barrier function. This process of barrier restoration and resealing of the gaps are facilitated by several naturally occurring barrier-enhancing molecules such as hepatocyte growth factor, sphingosine-1-phosphate, prostaglandins, oxidized phospholipids, and hyperosmolarity. Many of the barrier-protective agents are generated and released either in circulation by the ECs or other cells and in proximity to the disrupted endothelium. While mechanisms of EC barrier disruption have been extensively investigated, the process of barrier restoration of the endothelium is inadequately understood. Several lipid-derived mediators have been identified to facilitate the healing process and this article addresses the role of these lipid mediators in EC barrier restoration and gap closure with an emphasis on the signaling pathways related to lamellipodia formation and barrier restoration. Since no specific therapy is available currently to target the EC barrier disruption, an in-depth understanding of the mechanisms underlying the regulation of barrier restoration and stabilization of the junctions will lead to development of novel therapies.
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