title: A genetic variant of cortactin linked to acute lung injury impairs lamellipodia dynamics and endothelial wound healing.
abstract: Inflammatory mediators released in acute lung injury (ALI) trigger the disruption of interendothelial junctions, leading to loss of vascular barrier function, protein-rich pulmonary edema, and severe hypoxemia. Genetic signatures that predict patient recovery or disease progression are poorly defined, but recent genetic screening of ALI patients has identified an association between lung inflammatory disease and a single nucleotide polymorphism (SNP) in the gene for the actin-binding and barrier-regulatory protein cortactin. This study investigated the impact of this disease-linked cortactin variant on wound healing processes that may contribute to endothelial barrier restoration. A microfabricated platform was used to quantify wound healing in terms of gap closure speed, lamellipodia dynamics, and cell velocity. Overexpression of wild-type cortactin in endothelial cells (ECs) improved directional cell motility and enhanced lamellipodial protrusion length, resulting in enhanced gap closure rates. By contrast, the cortactin SNP impaired wound closure and cell locomotion, consistent with the observed reduction in lamellipodial protrusion length and persistence. Overexpression of the cortactin SNP in lung ECs mitigated the barrier-enhancing activity of sphingosine 1-phosphate. These findings suggest that this common cortactin variant may functionally contribute to ALI predisposition by impeding endothelial wound healing.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, Illinois;
authors.forename: Sangwook
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona;
authors.forename: Sara M
authors.initials: SM
authors.lastname: Camp
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, Illinois;
authors.forename: Arkaprava
authors.initials: A
authors.lastname: Dan
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona;
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois Hospital and Health Sciences System, Chicago, Illinois; and.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, Illinois; Department of Chemistry, University of Illinois, Urbana, Illinois leckband@illinois.edu.
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Leckband
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015824:Blood-Air Barrier / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002478:Cells, Cultured; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D014945:Wound Healing
chemical_list: C495868:CTTN protein, human; D051356:Cortactin; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: acute lung injury; cortactin; endothelial wound healing; wound healing assay