Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury.
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-kappaB 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
Janek
J
Department of Anesthesiology and Intensive Care Medicine, Tuebingen University Hospital, Tuebingen, Germany.
Schmit
Marthe A
MA
Morote-Garcia
Julio C
JC
Mirakaj
Valbona
V
Köhler
David
D
Glover
Louise
L
Eldh
Therese
T
Walter
Ulrich
U
Karhausen
Jörn
J
Colgan
Sean P
SP
Rosenberger
Peter
P
D000818:Animals; D002199:Capillary Permeability; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020545:Respiratory Mucosa / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha; D055397:Ventilator-Induced Lung Injury; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D000098662:Vasodilator-Stimulated Phosphoprotein
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