Role of focal adhesion kinase in burn induced gut epithelial barrier dysfunction

Abstract

Mucosal barrier failure is a critical pathological step in the development of multiple organ failure during severe burn injury and trauma. The opening of the epithelial barrier leads to increased leukocyte infiltration into the lamina propria and microbial translocation from the intestinal lumen. These events augment intestinal inflammation and contribute to the severity of trauma‐associated complications. The aim of the study was to characterize the role of focal adhesion kinase (FAK) in intestinal barrier dysfunction following thermal injury. Our data demonstrated that severe thermal injury significantly increased the gut lumen‐to‐blood transport of FITC‐dextran in mice. The effect was significantly attenuated by the inhibition of FAK with PF573228. Stimulation of mouse intestinal epithelial cells with TNFα/IFNγ caused a decrease in transcellular electric resistance coupled with downregulation of junctional proteins. The responses were prevented by the inhibition of either PTK6 or FAK. Western blot analysis showed that knocking down PTK6 in cells reduced TNFα/IFNγ mediated FAK activation via diminished detection of FAK phosphorylation at Y397. Reintroduction of active PTK6 to PTK6 deficient cells rescued FAK phosphorylation in response to TNFα/IFNγ. The results suggest that PTK6 dependent FAK phosphorylation plays an important role in gut barrier dysfunction during inflammatory injury.Support or Funding InformationVA BX000799, NIH HL120954