Non-canonical Wnt signaling contributes to ventilator-induced lung injury through upregulation of WISP1 expression

Yue Feng Xia, Jing Chang, Jin Feng Yang, Wen Ouyang, Bruce Pitt, Timothy Billiar, Li Ming Zhang

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Mechanical ventilation may cause ventilator-induced lung injury (VILI). Canonical Wnt signaling has been reported to serve an important role in the pathogenesis of VILI. Bioinformatics analysis revealed that canonical and non-canonical Wnt signaling pathways were activated in VILI. However, the role of non-canonical Wnt signaling in the pathogenesis of VILI remains unclear. The present study aimed to analyze the potential role of non-canonical Wnt signaling in VILI pathogenesis. Lung injury was assessed via Evans blue albumin permeability and histological scoring, as well as by inflammatory cytokine expression and total protein concentration in bronchoalveolar lavage fluid. The relative protein expression of canonical and non-canonical Wnt signaling pathway components were examined via western blotting and immunohistochemistry. The results demonstrated that 6 h of mechanical ventilation at low tidal volume (LTV; 6 ml/kg) or moderate tidal volume (MTV; 12 ml/kg) induced lung injury in sensitive A/J mice. Ventilation with MTV increased the protein levels of Wnt-induced secreted protein 1 (WISP1), Rho-associated protein kinase 1 (ROCK1), phosphorylated (p)-Ras homolog gene family, member A and p-C-Jun N-terminal kinase (JNK). Inhibition of ROCK1 by Y27632 and JNK by SP600125 attenuated MTV-induced lung injury and decreased the expression of proteins involved in non-canonical Wnt signaling, including WISP1. In conclusion, non-canonical Wnt signaling participates in VILI by modulating WISP1 expression, which has been previously noted as critical for VILI development. Therefore, the non-canonical Wnt signaling pathway may provide a preventive and therapeutic target in VILI.

Original languageEnglish
Pages (from-to)1217-1228
Number of pages12
JournalInternational Journal of Molecular Medicine
Issue number3
StatePublished - Mar 2019
Externally publishedYes


  • WNT1-inducible secreted protein 1
  • c-Jun N-terminal kinase
  • low tidal volume
  • moderate tidal volume
  • non-canonical Wnt signaling pathway
  • ventilator-induced lung injury


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