Molecular mechanisms in lipopolysaccharide-induced pulmonary endothelial barrier dysfunction

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Abstract

The confluent pulmonary endothelium plays an important role as a semi-permeable barrier between the vascular space of blood vessels and the underlying tissues, and it contributes to the maintenance of circulatory fluid homeostasis. Pulmonary endothelial barrier dysfunction is a pivotal early step in the development of a variety of high mortality diseases, such as acute lung injury (ALI). Endothelium barrier dysfunction in response to inflammatory or infectious mediators, including lipopolysaccharide (LPS), is accompanied by invertible cell deformation and interendothelial gap formation. However, specific pharmacological therapies aiming at ameliorating pulmonary endothelial barrier function in patients are still lacking. A full understanding of the fundamental mechanisms that are involved in the regulation of pulmonary endothelial permeability is essential for the development of barrier protective therapeutic strategies. Therefore, this review summarizes several important molecular mechanisms involved in LPS-induced changes in pulmonary endothelial barrier function. As for barrier-disruption, the activation of myosin light chain kinase (MLCK), RhoA and tyrosine kinases; increase of calcium influx; and apoptosis of the endothelium lead to an elevation of lung endothelial permeability. Additionally, the activation of Rac1, Cdc42, protease activated receptor 1 (PAR1) and adenosine receptors (ARs), as well as the increase of cyclic AMP and sphingosine-1-phosphate (S1P) content, protect against LPS-induced lung endothelial barrier dysfunction. Furthermore, current regulatory factors and strategies against the development of LPS-induced lung endothelial hyper-permeability are discussed.

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