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Fas activation alters tight junction proteins in acute lung injury
  1. Raquel Herrero1,2,
  2. Lucia Prados3,
  3. Antonio Ferruelo1,
  4. Ferranda Puig1,4,
  5. Rachele Pandolfi5,
  6. Raquel Guillamat-Prats1,4,
  7. Laura Moreno1,5,6,
  8. Gustavo Matute-Bello7,
  9. Antonio Artigas4,
  10. Andres Esteban1,8,
  11. José Ángel Lorente1,2,8
  1. 1 CIBER de Enfermedades Respiratorias, Instituto de Investigación Carlos III, Madrid, Spain
  2. 2 Department of Critical Care Medicine, Hospital Universitario de Getafe, Madrid, Spain
  3. 3 Laboratory of Biochemistry, Hospital Universitario de Getafe, Madrid, Spain
  4. 4 Critical Care Center, Corporació Sanitària i Universitària Parc Taul, Institut d’ Investigació i Innovació Parc Taulí, Barcelona, Spain
  5. 5 Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
  6. 6 Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
  7. 7 Center for Lung Biology, Division of Pulmonary and Critical Care Medicine, Department of Medicine, and the Medical Research Service of the VA Puget Sound Healthcare System., University of Washington, Seattle, Washington, USA
  8. 8 Universidad Europea, Madrid, Spain
  1. Correspondence to Dr Raquel Herrero, Department of Critical Care Medicine, Hospital Universitario de Getafe, Madrid 28905, Spain; raquelher{at}hotmail.com

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–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.

  • pulmonary oedema
  • innate immunity
  • ards

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Footnotes

  • RH and LP contributed equally.

  • Contributors Conception and design: RH. Acquisition, analysis and interpretation of data: all authors. Drafting and revising of the work: RH, LP, LM, GM-B and JAL. Final approval of the version: all authors.

  • Funding This work was supported by the Grants PI12/02451 and PI15/00482 (to RH) and PI15/01942 (to JAL) from the Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Madrid, Spain, and Fondos FEDER ’Una Manera de hacer Europa', and the Merit Award Number i01 BX002914 from the US Department of Veterans Affairs Biomedical Laboratory R&D (BLRD) Service (to GM-B). LM is a recipient of a Miguel Servet Fellowship (CP12/03304) from the Instituto de Salud Carlos III (Spain), and RP was supported by a research initiation grant from CIBERES.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval The animal protocol was approved by the Animal Care Committee of Hospital Universitario de Getafe (Madrid, Spain).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All the data from this work are freely available upon request.

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