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Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injury.
Crit Care. 2014 Oct 21; 18(5):568.CC

Abstract

INTRODUCTION

The mechanisms of lung repair and fibrosis in the acute respiratory distress syndrome (ARDS) are poorly known. Since the role of WNT/β-catenin signaling appears to be central to lung healing and fibrosis, we hypothesized that this pathway is activated very early in the lungs after sepsis.

METHODS

We tested our hypothesis using a three-step experimental design: (1) in vitro lung cell injury model with human bronchial epithelial BEAS-2B and lung fibroblasts (MRC-5) cells exposed to endotoxin for 18 hours; (2) an animal model of sepsis-induced ARDS induced by cecal ligation and perforation, and (3) lung biopsies from patients who died within the first 24 hours of septic ARDS. We examined changes in protein levels of target genes involved in the Wnt pathway, including WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP7), cyclin D1, and vascular endothelial growth factor (VEGF) by Western blotting and immunohistochemistry. Finally, we validated the main gene targets of this pathway in experimental animals and human lungs.

RESULTS

Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, total β-catenin, MMP7, cyclin D1, and VEGF increased after endotoxin stimulation in BEAS-2B and MRC-5 cells. Lungs from septic animals and from septic humans demonstrated acute lung inflammation, collagen deposition, and marked increase of WNT5A and MMP7 protein levels.

CONCLUSIONS

Our findings suggest that the WNT/β-catenin signaling pathway is activated very early in sepsis-induced ARDS and could play an important role in lung repair and fibrosis. Modulation of this pathway might represent a potential target for treatment for septic and ARDS patients.

Authors+Show Affiliations

CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jesus.villar54@gmail.com. Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain. jesus.villar54@gmail.com. Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada. jesus.villar54@gmail.com.CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. nuriaecb@gmail.com. Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain. nuriaecb@gmail.com.CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. shefloanse@hotmail.com. Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain. shefloanse@hotmail.com.CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. cflores@ull.edu.es. Research Unit, Hospital Universitario NS de Candelaria, Santa Cruz de Tenerife, Spain. cflores@ull.edu.es.Department of Anatomy, Pathology & Histology, Medical School University of La Laguna and Hospital Universitario de Canarias, La Laguna, Tenerife, Spain. soniagaher76@gmail.com.CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. fvallapa@gmail.com. Department of Anatomy, Pathology & Histology, Medical School University of La Laguna and Hospital Universitario de Canarias, La Laguna, Tenerife, Spain. fvallapa@gmail.com.CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. JLopezA@tauli.cat. Critical Care Center, Corporació Sanitaria Parc Taulí, Sabadell, Barcelona, Spain. JLopezA@tauli.cat.CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. lblanch@tauli.cat. Critical Care Center, Corporació Sanitaria Parc Taulí, Sabadell, Barcelona, Spain. lblanch@tauli.cat.Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada. lblanch@tauli.cat. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada. lblanch@tauli.cat.

Pub Type(s)

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

Language

eng

PubMed ID

25331176

Citation

Villar, Jesús, et al. "Early Activation of Pro-fibrotic WNT5A in Sepsis-induced Acute Lung Injury." Critical Care (London, England), vol. 18, no. 5, 2014, p. 568.
Villar J, Cabrera-Benítez NE, Ramos-Nuez A, et al. Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injury. Crit Care. 2014;18(5):568.
Villar, J., Cabrera-Benítez, N. E., Ramos-Nuez, A., Flores, C., García-Hernández, S., Valladares, F., López-Aguilar, J., Blanch, L., & Slutsky, A. S. (2014). Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injury. Critical Care (London, England), 18(5), 568. https://doi.org/10.1186/s13054-014-0568-z
Villar J, et al. Early Activation of Pro-fibrotic WNT5A in Sepsis-induced Acute Lung Injury. Crit Care. 2014 Oct 21;18(5):568. PubMed PMID: 25331176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injury. AU - Villar,Jesús, AU - Cabrera-Benítez,Nuria E, AU - Ramos-Nuez,Angela, AU - Flores,Carlos, AU - García-Hernández,Sonia, AU - Valladares,Francisco, AU - López-Aguilar,Josefina, AU - Blanch,Lluís, AU - Slutsky,Arthur S, Y1 - 2014/10/21/ PY - 2014/01/13/received PY - 2014/10/02/accepted PY - 2014/10/22/entrez PY - 2014/10/22/pubmed PY - 2015/10/20/medline SP - 568 EP - 568 JF - Critical care (London, England) JO - Crit Care VL - 18 IS - 5 N2 - INTRODUCTION: The mechanisms of lung repair and fibrosis in the acute respiratory distress syndrome (ARDS) are poorly known. Since the role of WNT/β-catenin signaling appears to be central to lung healing and fibrosis, we hypothesized that this pathway is activated very early in the lungs after sepsis. METHODS: We tested our hypothesis using a three-step experimental design: (1) in vitro lung cell injury model with human bronchial epithelial BEAS-2B and lung fibroblasts (MRC-5) cells exposed to endotoxin for 18 hours; (2) an animal model of sepsis-induced ARDS induced by cecal ligation and perforation, and (3) lung biopsies from patients who died within the first 24 hours of septic ARDS. We examined changes in protein levels of target genes involved in the Wnt pathway, including WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP7), cyclin D1, and vascular endothelial growth factor (VEGF) by Western blotting and immunohistochemistry. Finally, we validated the main gene targets of this pathway in experimental animals and human lungs. RESULTS: Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, total β-catenin, MMP7, cyclin D1, and VEGF increased after endotoxin stimulation in BEAS-2B and MRC-5 cells. Lungs from septic animals and from septic humans demonstrated acute lung inflammation, collagen deposition, and marked increase of WNT5A and MMP7 protein levels. CONCLUSIONS: Our findings suggest that the WNT/β-catenin signaling pathway is activated very early in sepsis-induced ARDS and could play an important role in lung repair and fibrosis. Modulation of this pathway might represent a potential target for treatment for septic and ARDS patients. SN - 1466-609X UR - https://www.unboundmedicine.com/medline/citation/25331176/Early_activation_of_pro_fibrotic_WNT5A_in_sepsis_induced_acute_lung_injury_ L2 - https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0568-z DB - PRIME DP - Unbound Medicine ER -