title: Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Tuebingen University Hospital, Tuebingen, Germany.
authors.forename: Janek
authors.initials: J
authors.lastname: Henes
authors.forename: Marthe A
authors.initials: MA
authors.lastname: Schmit
authors.forename: Julio C
authors.initials: JC
authors.lastname: Morote-Garcia
authors.forename: Valbona
authors.initials: V
authors.lastname: Mirakaj
authors.forename: David
authors.initials: D
authors.lastname: Köhler
authors.forename: Louise
authors.initials: L
authors.lastname: Glover
authors.forename: Therese
authors.initials: T
authors.lastname: Eldh
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Jörn
authors.initials: J
authors.lastname: Karhausen
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
mesh_terms: 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
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D000098662:Vasodilator-Stimulated Phosphoprotein
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Dec;291(6):L1232-45
references.pmid: 16891393
references.citation: Circ Res. 1998 Nov 30;83(11):1115-23
references.pmid: 9831706
references.citation: Am J Respir Cell Mol Biol. 1997 May;16(5):489-94
references.pmid: 9160829
references.citation: J Cell Physiol. 1995 Jun;163(3):510-22
references.pmid: 7775594
references.citation: J Biophys Biochem Cytol. 1961 Dec;11:571-605
references.pmid: 14468626
references.citation: FASEB J. 2002 Apr;16(6):583-5
references.pmid: 11919161
references.citation: Biochem Pharmacol. 1987 Nov 15;36(22):3809-13
references.pmid: 2446625
references.citation: Am J Physiol Cell Physiol. 2002 Jun;282(6):C1235-45
references.pmid: 11997237
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D86-9
references.pmid: 16381981
references.citation: Nat Rev Immunol. 2005 Sep;5(9):712-21
references.pmid: 16110315
references.citation: J Cell Biol. 2007 Nov 19;179(4):761-75
references.pmid: 17998398
references.citation: J Clin Invest. 1995 Aug;96(2):710-20
references.pmid: 7635964
references.citation: FASEB J. 2007 Aug;21(10):2613-21
references.pmid: 17412998
references.citation: J Immunol. 2007 Jul 15;179(2):1254-63
references.pmid: 17617618
references.citation: Nat Immunol. 2009 Feb;10(2):195-202
references.pmid: 19122655
references.citation: Physiol Rev. 2002 Jan;82(1):19-46
references.pmid: 11773608
references.citation: J Biol Chem. 2002 Nov 8;277(45):42596-602
references.pmid: 12202485
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1173-82
references.pmid: 16428270
references.citation: N Engl J Med. 2000 May 4;342(18):1334-49
references.pmid: 10793167
references.citation: Am J Physiol Cell Physiol. 2008 Jan;294(1):C178-88
references.pmid: 17989211
references.citation: Am J Physiol. 1992 Apr;262(4 Pt 2):H1238-47
references.pmid: 1566906
references.citation: Am J Physiol. 1991 Jun;260(6 Pt 2):F769-78
references.pmid: 2058700
references.citation: Curr Opin Cell Biol. 1997 Feb;9(1):86-92
references.pmid: 9013670
references.citation: J Clin Invest. 2007 Mar;117(3):703-11
references.pmid: 17318263
references.citation: Am J Respir Cell Mol Biol. 2006 Nov;35(5):519-27
references.pmid: 16741163
references.citation: N Engl J Med. 2005 Oct 20;353(16):1685-93
references.pmid: 16236739
references.citation: Am J Respir Crit Care Med. 1999 Jun;159(6):1849-61
references.pmid: 10351930
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Apr;288(4):L749-60
references.pmid: 15591411
references.citation: J Immunol. 2007 Jun 15;178(12):8127-37
references.pmid: 17548651
references.citation: J Am Soc Nephrol. 2005 Apr;16(4):986-96
references.pmid: 15743999
references.citation: Annu Rev Pathol. 2007;2:111-43
references.pmid: 18039095
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L807-15
references.pmid: 15951336
references.citation: J Clin Invest. 2006 Sep;116(9):2316-9
references.pmid: 16955131
references.citation: J Cell Physiol. 1986 Jul;128(1):96-104
references.pmid: 3722274
references.citation: J Clin Invest. 2008 Oct;118(10):3301-15
references.pmid: 18787641
references.citation: J Cell Biol. 2008 Jan 14;180(1):205-19
references.pmid: 18195108
references.citation: Am J Physiol. 1999 Jun;276(6):L989-98
references.pmid: 10362724
references.citation: J Card Surg. 1989 Jun;4(2):140-8
references.pmid: 2485155
references.citation: Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):2051-6
references.pmid: 10978248
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Jun;280(6):L1168-78
references.pmid: 11350795
references.citation: J Clin Invest. 1998 Aug 15;102(4):792-803
references.pmid: 9710448
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Oct;295(4):L718-24
references.pmid: 18708630
references.citation: J Exp Med. 1998 Oct 19;188(8):1433-43
references.pmid: 9782120
references.citation: J Clin Invest. 2002 Dec;110(11):1703-16
references.pmid: 12464676