title: Lumican regulates ventilation-induced epithelial-mesenchymal transition through extracelluar signal-regulated kinase pathway.
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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kweishan, Taoyuan, Taiwan; Department of Respiratory Therapy, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; Department of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Li-Fu
authors.initials: LF
authors.lastname: Li
authors.affiliation: Department of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Pao-Hsien
authors.initials: PH
authors.lastname: Chu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kweishan, Taoyuan, Taiwan; Department of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Cheng-Yiu
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Edith J. Crawley Vision Science Research Laboratory, Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH.
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
authors.affiliation: Department of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Meng-Chih
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Department of Respiratory Therapy, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; Department of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yung-Yang
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kweishan, Taoyuan, Taiwan. Electronic address: yang1946@adm.cgmh.org.tw.
authors.forename: Cheng-Ta
authors.initials: CT
authors.lastname: Yang
mesh_terms: D000818:Animals; D015820:Cadherins / Q000502:physiology; D054426:Chemokine CXCL2 / Q000502:physiology; D011508:Chondroitin Sulfate Proteoglycans / Q000172:deficiency / Q000502:physiology*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D007632:Keratan Sulfate / Q000172:deficiency / Q000502:physiology*; D000071234:Lumican; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012121:Respiration, Artificial / Q000009:adverse effects*; D013990:Tidal Volume / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D055397:Ventilator-Induced Lung Injury / Q000209:etiology* / Q000503:physiopathology*
chemical_list: D015820:Cadherins; D054426:Chemokine CXCL2; D011508:Chondroitin Sulfate Proteoglycans; C404915:Cxcl2 protein, mouse; D005419:Flavonoids; C000604307:Lum protein, mouse; D000071234:Lumican; D047428:Protein Kinase Inhibitors; D053773:Transforming Growth Factor beta1; D007632:Keratan Sulfate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one