@article {Herrero69, author = {Raquel Herrero and Lucia Prados and Antonio Ferruelo and Ferranda Puig and Rachele Pandolfi and Raquel Guillamat-Prats and Laura Moreno and Gustavo Matute-Bello and Antonio Artigas and Andres Esteban and Jos{\'e} {\'A}ngel Lorente}, title = {Fas activation alters tight junction proteins in acute lung injury}, volume = {74}, number = {1}, pages = {69--82}, year = {2019}, doi = {10.1136/thoraxjnl-2018-211535}, publisher = {BMJ Publishing Group Ltd}, abstract = {Background:The acute respiratory distress syndrome (ARDS) is characterized by protein-rich oedema in the alveolar spaces, a feature in which Fas-mediated apoptosis of the alveolar epithelium has been involved. Objective:To determine whether Fas activation increases protein permeability by mechanisms involving disruption of the paracellular tight junction (TJ) proteins in the pulmonary alveoli. Methods: Protein permeability and the expression of TJ proteins were assessed in vivo in wild-type and Fas-deficient lpr mice 16 hours after the intratracheal instillation of recombinant human soluble Fas ligand (rh-sFasL), and at different time points in vitro in human pulmonary alveolar epithelial cells (HPAEpiC) exposed to rh-sFasL Results:Activation of the Fas pathway increased protein permeability in mouse lungs and altered the expression of the TJ proteins occludin and zonula occludens-1 in the alveolar{\textendash}capillary membrane in vivo and in human alveolar epithelial cell monolayers in vitro. Blockade of caspase-3, but not inhibition of tyrosine kinase dependent pathways, prevented the alterations in TJ protein expression and permeability induced by the Fas/FasL system in human alveolar cell monolayers in vitro. We also observed that both the Fas-induced increase of protein permeability and disruption of TJ proteins occurred before cell death could be detected in the cell monolayers in vitro. Conclusion:Targeting caspase pathways could prevent the disruption of TJs and reduce the formation of lung oedema in the early stages of ARDS.}, issn = {0040-6376}, URL = {https://thorax.bmj.com/content/74/1/69}, eprint = {https://thorax.bmj.com/content/74/1/69.full.pdf}, journal = {Thorax} }