Tissue Factor: key to understanding ARDS?
A major pathologic feature of ARDS is activation of the Tissue Factor (TF) pathway of coagulation in the airspace.
TF is an integral membrane protein that both initiates the extrinsic coagulation cascade and serves several non-coagulant functions including promoting cell adhesion and migration through interactions with integrin proteins. For decades, procoagulant pathways, including the TF pathway, have been implicated as a mechanism of injury in ARDS. However, a number of clinical trails of anti-coagulants have not shown a benefit with this approach. One potential explanation is that TF in the airspace is protective in ARDS.
Our preliminary in vivo and in vitro data show that loss of lung epithelial, but not macrophage, TF causes loss of epithelial barrier integrity, decreased cell surface β1 integrin and abnormal cell adhesion. Conversely, overexpression of TF in alveolar epithelial type II cells restores barrier integrity. In addition, treatment with recombinant factor VII (rFVII), the primary TF ligand, into the airspace attenuates permeability in a mouse
model of ARDS. Together, these observations represent a major shift in understanding the role of the TF pathway in ARDS, a pathway that has almost universally been considered harmful.
Our lab is testing the hypotheses that loss of lung epithelial TF leads to loss of epithelial barrier integrity through disruption of integrin proteins and upregulation of TF in the airspace maintains epithelial barrier integrity in a direct lung injury model.
We also use a novel TF knockout lung epithelial cell line to study the molecular interactions between TF and β1 integrin and the role of TF in regulating epithelial barrier integrity by expressing a library of novel TF mutants.