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Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury

Janek Henes^*,1, Marthe A. Schmit^*,,1, Julio C. Morote-Garcia^*, Valbona Mirakaj^*, David Köhler^*, Louise Glover, Therese Eldh, Ulrich Walter^||, Jörn Karhausen^*, Sean P. Colgan and Peter Rosenberger^*,2

^* Department of Anesthesiology and Intensive Care Medicine and

Department of Radiation Oncology, Tuebingen University Hospital, Tuebingen, Germany;

Tieraerztliche Fakultaet, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany;

Mucosal Inflammation Program, University of Colorado Health Sciences Center, Denver, Colorado, USA; and

^|| Institute of Clinical Biochemistry and Pathobiochemistry and Division of Laboratory Medicine (IKBZ), University of Wuerzburg, Wuerzburg, Germany

² Correspondence: Department of Anesthesiology and Intensive Care Medicine, Tuebingen University Hospital, Hoppe- Seyler-Str. 3, D-72076 Tuebingen, Germany. E-mail: peter.rosenberger{at}medizin.uni-tuebingen.de

Acute lung injury (ALI) is an inflammatory disorder associated with reduced alveolar-capillary barrier function, increased pulmonary vascular permeability, and infiltration of leukocytes into the alveolar space. Pulmonary function might be compromised, its most severe form being the acute respiratory distress syndrome. A protein central to physiological barrier properties is vasodilator-stimulated phosphoprotein (VASP). Given the fact that VASP expression is reduced during periods of cellular hypoxia, we investigated the role of VASP during ALI. Initial studies revealed reduced VASP expressional levels through cytokines in vitro. Studies in the putative human VASP promoter identified NF-B as a key regulator of VASP transcription. This VASP repression results in increased paracellular permeability and migration of neutrophils in vitro. In a model of LPS-induced ALI, VASP^–/– mice demonstrated increased pulmonary damage compared with wild-type animals. These findings were confirmed in a second model of ventilator-induced lung injury. Studies employing bone marrow chimeric animals identified tissue-specific repression of VASP as the underlying cause of decreased barrier properties of the alveolar-capillary barrier during ALI. Taken together these studies identify tissue-specific VASP as a central protein in the control of the alveolar-capillary barrier properties during ALI.—Henes, J., Schmit, M. A., Morote-Garcia, J. C., Mirakaj, V., Köhler, D., Glover, L., Eldh, T., Walter, U., Karhausen, J., Colgan, S. P., Rosenberger, P. Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury.

Key Words: cytoskeleton • ALI • ventilator-induced lung injury • pulmonary inflammation • actin