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

Sangwook Choi, Sara M. Camp, Arkaprava Dan, Joe GN Garcia, Steven M. Dudek, Deborah E. Leckband

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)L983-L994
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume309
Issue number9
DOIs
StatePublished - 2015

Fingerprint

Cortactin
Pseudopodia
Acute Lung Injury
Wound Healing
Single Nucleotide Polymorphism
Cell Movement
Endothelial Cells
Genetic Testing
Pulmonary Edema
Lung Diseases
Blood Vessels
Disease Progression
Actins
Proteins
Lung
Wounds and Injuries

Keywords

  • Acute lung injury
  • Cortactin
  • Endothelial wound healing
  • Wound healing assay

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

A genetic variant of cortactin linked to acute lung injury impairs lamellipodia dynamics and endothelial wound healing. / Choi, Sangwook; Camp, Sara M.; Dan, Arkaprava; Garcia, Joe GN; Dudek, Steven M.; Leckband, Deborah E.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 309, No. 9, 2015, p. L983-L994.

Research output: Contribution to journalArticle

Choi, Sangwook ; Camp, Sara M. ; Dan, Arkaprava ; Garcia, Joe GN ; Dudek, Steven M. ; Leckband, Deborah E. / A genetic variant of cortactin linked to acute lung injury impairs lamellipodia dynamics and endothelial wound healing. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015 ; Vol. 309, No. 9. pp. L983-L994.
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