PT  - JOURNAL ARTICLE
AU  - Herrero, Raquel
AU  - Prados, Lucia
AU  - Ferruelo, Antonio
AU  - Puig, Ferranda
AU  - Pandolfi, Rachele
AU  - Guillamat-Prats, Raquel
AU  - Moreno, Laura
AU  - Matute-Bello, Gustavo
AU  - Artigas, Antonio
AU  - Esteban, Andres
AU  - Lorente, José Ángel
TI  - Fas activation alters tight junction proteins in acute lung injury
AID  - 10.1136/thoraxjnl-2018-211535
DP  - 2019 Jan 01
TA  - Thorax
PG  - 69--82
VI  - 74
IP  - 1
4099  - http://thorax.bmj.com/content/74/1/69.short
4100  - http://thorax.bmj.com/content/74/1/69.full
SO  - Thorax2019 Jan 01; 74
AB  - 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–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.