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Original Research: Critical Care |

Lumican Regulates Ventilation-Induced Epithelial-Mesenchymal Transition Through Extracelluar Signal-Regulated Kinase PathwayLumican and Ventilator-Induced Lung Injury

Li-Fu Li, MD; Pao-Hsien Chu, MD, FCCP; Cheng-Yiu Hung, MD; Winston W.-Y. Kao, MD; Meng-Chih Lin, MD; Yung-Yang Liu, MD; Cheng-Ta Yang, MD
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine (Drs Li, Hung, and Yang) and Department of Respiratory Therapy (Drs Li, and Yang), Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; Department of Medicine (Drs Li, Chu, Hung, Yang, and Lin), Chang Gung University, Kweishan, Taoyuan, Taiwan; First Cardiovascular Division (Dr Chu), Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; Edith J. Crawley Vision Science Research Laboratory (Dr Kao), Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH; Division of Pulmonary and Critical Care Medicine (Dr Lin), Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Chest Department (Dr Liu), Taipei Veterans General Hospital, Taipei, Taiwan; and Institute of Clinical Medicine (Dr Liu), National Yang-Ming University, Taipei, Taiwan.

Correspondence to: Cheng-Ta Yang, MD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, 5 Fu-Hsing St, Kweishan, Taoyuan, 333, Taiwan; e-mail: yang1946@adm.cgmh.org.tw


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Funding/Support: The study was supported by the National Science Council [98-2314-B-182A-084-MY3 and 101-2314-B-182A-088-MY3], Chang Gung Research Project [3A0711 (to Dr Li) 97-2314-B-182-028-MY2, and 99-2314-B-182-042-MY3 (to Dr Chu)]; National Institutes of Health, National Eye Institute [Grant EY011845], Research to Prevent Blindness; and Ohio Lions Eye Research Foundation (to Dr Kao).


Chest. 2013;143(5):1252-1260. doi:10.1378/chest.12-2058
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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.

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