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Activation of the Wnt/β-catenin signaling pathway by mechanical ventilation is associated with ventilator-induced pulmonary fibrosis in healthy lungs.
PLoS One. 2011; 6(9):e23914.Plos

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.

METHODOLOGY/PRINCIPAL FINDINGS

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/SIGNIFICANCE

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+Show Affiliations

CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jesus.villar54@gmail.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21935365

Citation

Villar, Jesús, et al. "Activation of the Wnt/β-catenin Signaling Pathway By Mechanical Ventilation Is Associated With Ventilator-induced Pulmonary Fibrosis in Healthy Lungs." PloS One, vol. 6, no. 9, 2011, pp. e23914.
Villar J, Cabrera NE, Valladares F, et al. Activation of the Wnt/β-catenin signaling pathway by mechanical ventilation is associated with ventilator-induced pulmonary fibrosis in healthy lungs. PLoS One. 2011;6(9):e23914.
Villar, J., Cabrera, N. E., Valladares, F., Casula, M., Flores, C., Blanch, L., Quilez, M. E., Santana-Rodríguez, N., Kacmarek, R. M., & Slutsky, A. S. (2011). Activation of the Wnt/β-catenin signaling pathway by mechanical ventilation is associated with ventilator-induced pulmonary fibrosis in healthy lungs. PloS One, 6(9), e23914. https://doi.org/10.1371/journal.pone.0023914
Villar J, et al. Activation of the Wnt/β-catenin Signaling Pathway By Mechanical Ventilation Is Associated With Ventilator-induced Pulmonary Fibrosis in Healthy Lungs. PLoS One. 2011;6(9):e23914. PubMed PMID: 21935365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the Wnt/β-catenin signaling pathway by mechanical ventilation is associated with ventilator-induced pulmonary fibrosis in healthy lungs. AU - Villar,Jesús, AU - Cabrera,Nuria E, AU - Valladares,Francisco, AU - Casula,Milena, AU - Flores,Carlos, AU - Blanch,Lluís, AU - Quilez,María Elisa, AU - Santana-Rodríguez,Norberto, AU - Kacmarek,Robert M, AU - Slutsky,Arthur S, Y1 - 2011/09/15/ PY - 2011/04/18/received PY - 2011/07/27/accepted PY - 2011/9/22/entrez PY - 2011/9/22/pubmed PY - 2012/4/14/medline SP - e23914 EP - e23914 JF - PloS one JO - PLoS One VL - 6 IS - 9 N2 - 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/21935365/Activation_of_the_Wnt/β_catenin_signaling_pathway_by_mechanical_ventilation_is_associated_with_ventilator_induced_pulmonary_fibrosis_in_healthy_lungs_ L2 - https://dx.plos.org/10.1371/journal.pone.0023914 DB - PRIME DP - Unbound Medicine ER -