This Research Topic is part of the Molecular Mechanisms of Lung Endothelial Permeability series:
Molecular Mechanisms of Lung Endothelial PermeabilityLung endothelium regulates movement of fluid, macromolecules, and leukocytes into the interstitium and subsequently into the alveolar air spaces. The endothelial cells (EC) lining the vessels are in close contact with each other forming a tight barrier. Any breach in the endothelial barrier results in the movement of fluid and macromolecules into the interstitium and pulmonary air spaces causing pulmonary edema. Therefore, the integrity of the pulmonary EC monolayer is a critical requirement for preservation of pulmonary function. Disruption of lung endothelial barrier occurs during inflammatory disease states such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which remains a major cause of morbidity and mortality with an overall mortality rate of 30-40%. Barrier maintenance is determined by the equilibrium of competing contractile forces, which generate centripetal tension via activation of actomyosin contractile machinery and adhesive cell-cell and cell-matrix tethering forces, which depends upon adhesive molecules located at cell-cell and cell-matrix contacts. Both competing forces are linked through actin microfilaments, which are connected to multiple membrane adhesive proteins of the zona occludens and zona adherens, glycocalyx components, functional intercellular proteins and focal adhesion complex proteins. Reorganization of the endothelial cytoskeleton, mainly actin filaments and microtubules, via activation of c-Src and Rho signaling and (or) intracellular Ca2+ influx leads to alteration of cell shape and provides a structural basis for the increase of vascular permeability. While many edemagenic agonists like thrombin, endotoxin increase endothelial permeability via activation of EC contractility, some others like phorbol esters and pro-inflammatory cytokines increase EC permeability without increase in contraction, however, all of them weaken EC barrier via decreased endothelial junctions and cell-matrix contacts. While the majority of transendothelial trafficking of fluids and leukocytes occurs by the paracellular pathway, growing evidence has also highlighted the importance of the transcellular pathway in mediating albumin transport via caveolae-dependent transcytosis. Caveolae, the lipid raft plasma membrane structures, are responsible for the vesicular transfer of albumin, albumin-bound ligands from the luminal to the basal surface of EC. While regulating independently both para- and transcellular pathways are interconnected in the regulation of tissue fluid homeostasis
This Research Topic will provide an overview of recent studies in the field of lung endothelial permeability with the goal to advance our knowledge of the mechanisms of pulmonary endothelial barrier regulation. We hope that it will help to identify novel strategies and pharmacologic agonists for therapeutic intervention in ALI/ARDS.
This Research Topic is part of the Molecular Mechanisms of Lung Endothelial Permeability series:
Molecular Mechanisms of Lung Endothelial PermeabilityLung endothelium regulates movement of fluid, macromolecules, and leukocytes into the interstitium and subsequently into the alveolar air spaces. The endothelial cells (EC) lining the vessels are in close contact with each other forming a tight barrier. Any breach in the endothelial barrier results in the movement of fluid and macromolecules into the interstitium and pulmonary air spaces causing pulmonary edema. Therefore, the integrity of the pulmonary EC monolayer is a critical requirement for preservation of pulmonary function. Disruption of lung endothelial barrier occurs during inflammatory disease states such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which remains a major cause of morbidity and mortality with an overall mortality rate of 30-40%. Barrier maintenance is determined by the equilibrium of competing contractile forces, which generate centripetal tension via activation of actomyosin contractile machinery and adhesive cell-cell and cell-matrix tethering forces, which depends upon adhesive molecules located at cell-cell and cell-matrix contacts. Both competing forces are linked through actin microfilaments, which are connected to multiple membrane adhesive proteins of the zona occludens and zona adherens, glycocalyx components, functional intercellular proteins and focal adhesion complex proteins. Reorganization of the endothelial cytoskeleton, mainly actin filaments and microtubules, via activation of c-Src and Rho signaling and (or) intracellular Ca2+ influx leads to alteration of cell shape and provides a structural basis for the increase of vascular permeability. While many edemagenic agonists like thrombin, endotoxin increase endothelial permeability via activation of EC contractility, some others like phorbol esters and pro-inflammatory cytokines increase EC permeability without increase in contraction, however, all of them weaken EC barrier via decreased endothelial junctions and cell-matrix contacts. While the majority of transendothelial trafficking of fluids and leukocytes occurs by the paracellular pathway, growing evidence has also highlighted the importance of the transcellular pathway in mediating albumin transport via caveolae-dependent transcytosis. Caveolae, the lipid raft plasma membrane structures, are responsible for the vesicular transfer of albumin, albumin-bound ligands from the luminal to the basal surface of EC. While regulating independently both para- and transcellular pathways are interconnected in the regulation of tissue fluid homeostasis
This Research Topic will provide an overview of recent studies in the field of lung endothelial permeability with the goal to advance our knowledge of the mechanisms of pulmonary endothelial barrier regulation. We hope that it will help to identify novel strategies and pharmacologic agonists for therapeutic intervention in ALI/ARDS.
