Cytoskeletal regulation of pulmonary vascular permeability.
Dudek, Steven M, and Joe G. N. Garcia.
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School
of Medicine, Baltimore, Maryland 21224
APStracts 8:0342A, 2001.
The endothelial cell (EC) lining of the pulmonary vasculature forms a semipermeable
barrier between the blood and the interstitium of the lung. Disruption of this barrier
occurs during inflammatory disease states such as acute lung injury and acute respiratory
distress syndrome and results in the movement of fluid and macromolecules into the
interstitium and pulmonary airspaces. These processes significantly contribute to the high
morbidity and mortality of patients afflicted with acute lung injury. The critical
importance of pulmonary vascular barrier function is shown by the balance between
competing EC contractile forces, which generate centripetal tension, and adhesive cell-
cell and cell-matrix tethering forces, which regulate cell shape. Both competing forces in
this model are intimately linked through the endothelial cytoskeleton, a complex network
of actin microfilaments, microtubules, and intermediate filaments, which combine to
regulate shape change and transduce signals within and between EC. A key EC
contractile event in several models of agonist-induced barrier dysfunction is the
phosphorylation of regulatory myosin light chains catalyzed by Ca2+/calmodulin-
dependent myosin light chain kinase and/or through the activity of the Rho/Rho kinase
pathway. Intercellular contacts along the endothelial monolayer consist primarily of two
types of complexes (adherens junctions and tight junctions), which link to the actin
cytoskeleton to provide both mechanical stability and transduction of extracellular signals
into the cell. Focal adhesions provide additional adhesive forces in barrier regulation by
forming a critical bridge for bidirectional signal transduction between the actin
cytoskeleton and the cell-matrix interface. Increasingly, the effects of mechanical forces
such as shear stress and ventilator-induced stretch on EC barrier function are being
recognized. The critical role of the endothelial cytoskeleton in integrating these multiple
aspects of pulmonary vascular permeability provides a fertile area for the development of
clinically important barrier-modulating therapies.
APS Manuscript Number A403-1.
Article publication pending J Appl Physiol
ISSN 1080-4757 Copyright 2001 The American Physiological Society.
Published in APStracts on 29 June 2001