Abstract
IntroductionThe 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.MethodsWe 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.ResultsProtein 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0568-z) contains supplementary material, which is available to authorized users.
Highlights
The mechanisms of lung repair and fibrosis in the acute respiratory distress syndrome (ARDS) are poorly known
matrix metalloproteinase-7 (MMP7) is a target gene of the wingless integration (Wnt) signaling pathway found on the surface of lung epithelial cells and is a key regulator of pulmonary fibrosis [16]
The active form of the MMP7 protein was increased in both MRC-5 and BEAS-2B cells stimulated with LPS
Summary
The mechanisms of lung repair and fibrosis in the acute respiratory distress syndrome (ARDS) are poorly known. Wnt/β-catenin signaling stimulates tissue remodeling and wound closure, or tissue remodeling and destruction through matrix metallopeptidases (MMPs) and other gene products [14]. This activation stimulates many of the pro-inflammatory cytokines participating in inflammationmediated lung destruction and hyaline membrane formation [12], and induces expression of growth-associated genes such as cyclin D1 and vascular endothelial growth factor (VEGF) [15]. MMP7 ( known as matrilysin) is a target gene of the Wnt signaling pathway found on the surface of lung epithelial cells and is a key regulator of pulmonary fibrosis [16]
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