title: Activation of the Wnt/β-catenin signaling pathway by mechanical ventilation is associated with ventilator-induced pulmonary fibrosis in healthy lungs.
abstract: BACKGROUND
  Mechanical ventilation (MV) with high tidal volumes (V(T)) can cause or aggravate lung damage, so-called ventilator induced lung injury (VILI). The relationship between specific mechanical events in the lung and the cellular responses that result in VILI remains incomplete. Since activation of Wnt/β-catenin signaling has been suggested to be central to mechanisms of lung healing and fibrosis, we hypothesized that the Wnt/β-catenin signaling plays a role during VILI.
  
  
  RESULTS
  Prospective, randomized, controlled animal study using adult, healthy, male Sprague-Dawley rats. Animals (n = 6/group) were randomized to spontaneous breathing or two strategies of MV for 4 hours: low tidal volume (V(T)) (6 mL/kg) or high V(T) (20 mL/kg). Histological evaluation of lung tissue, measurements of WNT5A, total β-catenin, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP-7), cyclin D1, vascular endothelial growth factor (VEGF), and axis inhibition protein 2 (AXIN2) protein levels by Western blot, and WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, and AXIN2 immunohistochemical localization in the lungs were analyzed. High-V(T) MV caused lung inflammation and perivascular edema with cellular infiltrates and collagen deposition. Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 in the lungs were increased in all ventilated animals although high-V(T) MV was associated with significantly higher levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 levels.
  
  
  CONCLUSIONS
  Our findings demonstrate that the Wnt/β-catenin signaling pathway is modulated very early by MV in lungs without preexistent lung disease, suggesting that activation of this pathway could play an important role in both VILI and lung repair. Modulation of this pathway might represent a therapeutic option for prevention and/or management of VILI.
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jesus.villar54@gmail.com
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Cabrera
authors.forename: Francisco
authors.initials: F
authors.lastname: Valladares
authors.forename: Milena
authors.initials: M
authors.lastname: Casula
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
authors.forename: Lluís
authors.initials: L
authors.lastname: Blanch
authors.forename: María Elisa
authors.initials: ME
authors.lastname: Quilez
authors.forename: Norberto
authors.initials: N
authors.lastname: Santana-Rodríguez
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kacmarek
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005740:Gases; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial; D015398:Signal Transduction; D013997:Time Factors; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism*; D012122:Ventilators, Mechanical; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D005740:Gases; D051153:Wnt Proteins; D051176:beta Catenin