Lumican regulates ventilation-induced epithelial-mesenchymal transition through extracelluar signal-regulated kinase pathway

F. Li, Pao Hsien Chu, Cheng Yiu Hung, Winston W.Y. Kao, Meng Chih Lin, Yung Yang Liu, Cheng Ta Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

30 Scopus citations

Abstract

Background: Mechanical ventilation used in patients with acute lung injury can damage pulmonary epithelial cells through production of inflammatory cytokines and excess deposition of the extracellular matrix protein lumican. Lumican participates in macrophage inflammatory protein (MIP)-2 and transforming growth factor-β1 (TGF-β1) signaling during the fibroproliferative phase of acute lung injury, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and lung injury are unclear. We hypothesized that lung damage and EMT by high tidal volume (VT) mechanical stretch causes upregulation of lumican that modulates MIP-2 and TGF-β1 through the extracellular signal-regulated kinase (ERK)1/2 pathway. Methods: Male C57BL/6 mice (either wild type or lumican null) aged 3 months and weighing between 25 and 30 g were exposed to low VT (6 mL/kg) or high VT (30 mL/kg) mechanical ventilation with room air for 2 to 8 h. Nonventilated mice were used as control subjects. Results: We found that high VT mechanical ventilation increased microvascular permeability, neutrophil influx, production of free radicals, MIP-2 and TGF-β1 proteins, positive staining of α-smooth muscle actin and S100A4/fibroblast-specific protein-1, Masson trichrome staining and extracellular collagen, and activation of lumican and ERK1/2 in wild-type mice. Decreased staining of the epithelial marker E-cadherin was also observed. Mechanical stretch-augmented EMT was attenuated with lumican-deficient mice and pharmacologic inhibition of ERK1/2 activity by PD98059. Conclusions: The data suggest that lumican promotes high VT mechanical ventilation-induced lung injury and EMT through the activation of the ERK1/2 pathway.

Original languageEnglish
Pages (from-to)1252-1260
Number of pages9
JournalChest
Volume143
Issue number5
DOIs
StatePublished - 05 2013

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