Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injury

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• 作者：Jes煤s Villar (1) (2) (3)
  Nuria E Cabrera-Ben铆tez (1) (2)
  Angela Ramos-Nuez (1) (2)
  Carlos Flores (1) (4)
  Sonia Garc铆a-Hern谩ndez (5)
  Francisco Valladares (1) (5)
  Josefina L贸pez-Aguilar (1) (6)
  Llu铆s Blanch (1) (6)
  Arthur S Slutsky (3) (7)
  
  1. CIBER de Enfermedades Respiratorias ; Instituto de Salud Carlos III ; Madrid ; Spain
  2. Multidisciplinary Organ Dysfunction Evaluation Research Network ; Research Unit ; Hospital Universitario Dr. Negrin ; Las Palmas de Gran Canaria ; Spain
  3. Keenan Research Center for Biomedical Science ; Li Ka Shing Knowledge Institute ; St. Michael鈥檚 Hospital ; Toronto ; Canada
  4. Research Unit ; Hospital Universitario NS de Candelaria ; Santa Cruz de Tenerife ; Spain
  5. Department of Anatomy ; Pathology & Histology ; Medical School University of La Laguna and Hospital Universitario de Canarias ; La Laguna ; Tenerife ; Spain
  6. Critical Care Center ; Corporaci贸 Sanitaria Parc Taul铆 ; Sabadell ; Barcelona ; Spain
  7. Interdepartmental Division of Critical Care Medicine ; University of Toronto ; Toronto ; ON ; Canada
  
• 刊名：Critical Care
• 出版年：2014
• 出版时间：October 2014
• 年：2014
• 卷：18
• 期：5
• 全文大小：1,953 KB
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• 刊物主题：Intensive / Critical Care Medicine; Emergency Medicine;
• 出版者：BioMed Central
• ISSN：1364-8535

文摘

Introduction The mechanisms of lung repair and fibrosis in the acute respiratory distress syndrome (ARDS) are poorly known. Since the role of WNT/尾-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聽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聽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) 尾-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) 尾-catenin, total 尾-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/尾-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.