Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injuryReport as inadecuate




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Critical Care

, 18:568

First Online: 21 October 2014Received: 13 January 2014Accepted: 02 October 2014

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.

AbbreviationsARDSacute respiratory distress syndrome

CLPcecal ligation and puncture

FBSfetal bovine serum

LPSlipopolysaccharide

MMPmetallopeptidase

MMP7metallopeptidase or metalloproteinase 7 also known as matrilysin

VEGFvascular endothelial growth factor

WNT5Awingless-type integration site family, member 5A

Electronic supplementary materialThe online version of this article doi:10.1186-s13054-014-0568-z contains supplementary material, which is available to authorized users.

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Author: Jesús Villar - Nuria E Cabrera-Benítez - Angela Ramos-Nuez - Carlos Flores - Sonia García-Hernández - Francisco Vallada

Source: https://link.springer.com/







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