title: Neuronal Wiskott-Aldrich syndrome protein regulates TGF-β1-mediated lung vascular permeability.
abstract: TGF-β1 induces an increase in paracellular permeability and actin stress fiber formation in lung microvascular endothelial and alveolar epithelial cells via small Rho GTPase. The molecular mechanism involved is not fully understood. Neuronal Wiskott-Aldrich syndrome protein (N-WASP) has an essential role in actin structure dynamics. We hypothesized that N-WASP plays a critical role in these TGF-β1-induced responses. In these cell monolayers, we demonstrated that N-WASP down-regulation by short hairpin RNA prevented TGF-β1-mediated disruption of the cortical actin structure, actin stress filament formation, and increased permeability. Furthermore, N-WASP down-regulation blocked TGF-β1 activation mediated by IL-1β in alveolar epithelial cells, which requires actin stress fiber formation. Control short hairpin RNA had no effect on these TGF-β1-induced responses. TGF-β1-induced phosphorylation of Y256 of N-WASP via activation of small Rho GTPase and focal adhesion kinase mediates TGF-β1-induced paracellular permeability and actin cytoskeleton dynamics. In vivo, compared with controls, N-WASP down-regulation increases survival and prevents lung edema in mice induced by bleomycin exposure-a lung injury model in which TGF-β1 plays a critical role. Our data indicate that N-WASP plays a crucial role in the development of TGF-β1-mediated acute lung injury by promoting pulmonary edema via regulation of actin cytoskeleton dynamics.-Wagener, B. M., Hu, M., Zheng, A., Zhao, X., Che, P., Brandon, A., Anjum, N., Snapper, S., Creighton, J., Guan, J.-L., Han, Q., Cai, G.-Q., Han, X., Pittet, J.-F., Ding, Q. Neuronal Wiskott-Aldrich syndrome protein regulates TGF-β1-mediated lung vascular permeability.
authors.affiliation: Division of Critical Care, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Brant M
authors.initials: BM
authors.lastname: Wagener
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Anni
authors.initials: A
authors.lastname: Zheng
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China;
authors.forename: Xueke
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Division of Neurology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Pulin
authors.initials: P
authors.lastname: Che
authors.affiliation: Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Angela
authors.initials: A
authors.lastname: Brandon
authors.affiliation: Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Naseem
authors.initials: N
authors.lastname: Anjum
authors.affiliation: Department of Pathology, Harvard University, Boston, Massachusetts, USA;
authors.forename: Scott
authors.initials: S
authors.lastname: Snapper
authors.affiliation: Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Judy
authors.initials: J
authors.lastname: Creighton
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA;
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Qimei
authors.initials: Q
authors.lastname: Han
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Cai
authors.affiliation: Division of Neurology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
authors.forename: Xiaosi
authors.initials: X
authors.lastname: Han
authors.affiliation: Division of Critical Care, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA jpittet@uabmc.edu.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pittet
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA qding@uab.edu.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D002199:Capillary Permeability / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D008168:Lung / Q000098:blood supply*; D055370:Lung Injury / Q000139:chemically induced; D051379:Mice; D009474:Neurons; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D001761:Bleomycin
keywords: FAK; IL-1β; acute lung injury; cytoskeletal dynamics; small Rho GTPases