Intensive Care Medicine

, Volume 37, Issue 7, pp 1201–1209 | Cite as

WNT/β-catenin signaling is modulated by mechanical ventilation in an experimental model of acute lung injury

  • Jesús VillarEmail author
  • Nuria E. Cabrera
  • Milena Casula
  • Francisco Valladares
  • Carlos Flores
  • Josefina López-Aguilar
  • Lluis Blanch
  • Haibo Zhang
  • Robert M. Kacmarek
  • Arthur S. Slutsky



The mechanisms involved in lung injury progression during acute lung injury (ALI) are still poorly understood. Because WNT/β-catenin signaling has been shown to be involved in epithelial cell injury and hyperplasia during inflammation and sepsis, we hypothesized that it would be modulated by mechanical ventilation (MV) in an experimental model of sepsis-induced ALI.


This study was a prospective, randomized, controlled animal study performed using adult male Sprague–Dawley rats. Sepsis was induced by cecal ligation and perforation. At 18 h, surviving animals were randomized to spontaneous breathing or two strategies of MV for 4 h: low tidal volume (V T) (6 ml/kg) plus 10 cmH2O of positive end-expiratory pressure (PEEP) versus high (20 ml/kg) tidal volume (V T) with zero PEEP. Histological evaluation, measurements of WNT5A, total β-catenin, and matrix metalloproteinase-7 (MMP7) protein levels by Western blot, and their immunohistochemical localization in the lungs were analyzed.


Sepsis and high-V T MV caused lung inflammation and perivascular edema with cellular infiltrates and collagen deposition. Protein levels of WNT5A, β-catenin, and MMP7 in the lungs were increased in animals with sepsis-induced ALI. High-V T MV was associated with higher levels of WNT5A, β-catenin, and MMP7 protein levels (p < 0.001), compared to healthy control animals. By contrast, low-V T MV markedly reduced WNT5A, β-catenin, and MMP7 protein levels (p < 0.001).


Our findings demonstrate that the WNT/β-catenin signaling pathway is modulated early during sepsis and ventilator-induced lung injury, suggesting that activation of this pathway could play an important role in both lung injury progression and repair.


Acute lung injury WNT/β-catenin pathway Ventilator-induced lung injury Metalloproteinase 



Supported by grants from Ministry of Science of Spain (SAF 2004-06833), Instituto de Salud Carlos III of Spain (PI 10/0393), the Canadian Institutes of Health Research, FUNCIS (53/04), and by a specific agreement between Instituto de Salud Carlos III and FUNCIS (EMER07/001) under the ENCYT 2015 framework.

Supplementary material

134_2011_2234_MOESM1_ESM.doc (401 kb)
Supplementary material 1 (DOC 401 kb)


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Copyright information

© Copyright jointly held by Springer and ESICM 2011

Authors and Affiliations

  • Jesús Villar
    • 1
    • 2
    • 3
    Email author
  • Nuria E. Cabrera
    • 1
    • 2
  • Milena Casula
    • 1
    • 2
  • Francisco Valladares
    • 1
    • 4
  • Carlos Flores
    • 1
    • 5
  • Josefina López-Aguilar
    • 1
    • 6
  • Lluis Blanch
    • 1
    • 6
  • Haibo Zhang
    • 3
  • Robert M. Kacmarek
    • 7
  • Arthur S. Slutsky
    • 3
    • 8
    • 9
  1. 1.CIBER de Enfermedades RespiratoriasInstituto de Salud Carlos IIIMadridSpain
  2. 2.Multidisciplinary Organ Dysfunction Evaluation Research Network, Research UnitHospital Universitario Dr. NegrinLas Palmas de Gran CanariaSpain
  3. 3.Keenan Research Center at the Li Ka Shing Knowledge Institute of St. Michael’s HospitalTorontoCanada
  4. 4.Department of Anatomy, Pathology and HistologyUniversity of La LagunaTenerifeSpain
  5. 5.Research UnitHospital Universitario N.S. de CandelariaTenerifeSpain
  6. 6.Critical Care Center, Corporació Sanitaria Parc TaulíSabadellSpain
  7. 7.Department of Respiratory CareMassachusetts General HospitalBostonUSA
  8. 8.Interdepartmental Division of Critical Care MedicineUniversity of TorontoTorontoCanada
  9. 9.King Saud UniversityRiyadhSaudi Arabia

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