A genetic variant of cortactin linked to acute lung injury impairs lamellipodia dynamics and endothelial wound healing.

TitleA genetic variant of cortactin linked to acute lung injury impairs lamellipodia dynamics and endothelial wound healing.
Publication TypeJournal Article
Year of Publication2015
AuthorsChoi S, Camp SM, Dan A, Garcia JGN, Dudek SM, Leckband DE
JournalAm J Physiol Lung Cell Mol Physiol
Volume309
Issue9
PaginationL983-94
Date Published2015 Nov 01
ISSN Number1522-1504
KeywordsAcute Lung Injury, Animals, Blood-Air Barrier, Cattle, Cells, Cultured, Cortactin, Endothelial Cells, Humans, Lysophospholipids, Polymorphism, Single Nucleotide, Pseudopodia, Sphingosine, Wound Healing
Abstract

<p>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.</p>

DOI10.1152/ajplung.00062.2015
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID26361873
PubMed Central IDPMC4628987
Grant ListP01 HL-58064 / HL / NHLBI NIH HHS / United States
R01 HL-88144 / HL / NHLBI NIH HHS / United States
R56 HL088144 / HL / NHLBI NIH HHS / United States
5R01 GM-097443 / GM / NIGMS NIH HHS / United States
R01 HL091889 / HL / NHLBI NIH HHS / United States