Li-Fu Li1, Pao-Hsien Chu2, Cheng-Yiu Hung3, Winston W-Y Kao4, Meng-Chih Lin5, Yung-Yang Liu6, Cheng-Ta Yang7. 1. 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. 2. Department of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan. 3. Division of Pulmonary and Critical Care Medicine, Kweishan, Taoyuan, Taiwan; Department of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan. 4. Edith J. Crawley Vision Science Research Laboratory, Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH. 5. Department of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan. 6. 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. 7. Division of Pulmonary and Critical Care Medicine, Kweishan, Taoyuan, Taiwan. Electronic address: yang1946@adm.cgmh.org.tw.
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.
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: William E Lawson; Vasiliy V Polosukhin; Ornella Zoia; Georgios T Stathopoulos; Wei Han; David Plieth; James E Loyd; Eric G Neilson; Timothy S Blackwell Journal: Am J Respir Crit Care Med Date: 2004-12-23 Impact factor: 21.405
Authors: S Ying; A Shiraishi; C W Kao; R L Converse; J L Funderburgh; J Swiergiel; M R Roth; G W Conrad; W W Kao Journal: J Biol Chem Date: 1997-11-28 Impact factor: 5.157
Authors: Nuria E Cabrera-Benítez; Matteo Parotto; Martin Post; Bing Han; Peter M Spieth; Wei-Erh Cheng; Francisco Valladares; Jesús Villar; Mingayo Liu; Masaaki Sato; Haibo Zhang; Arthur S Slutsky Journal: Crit Care Med Date: 2012-02 Impact factor: 7.598
Authors: Ivana Mižíková; Flore Lesage; Chanele Cyr-Depauw; David P Cook; Maria Hurskainen; Satu M Hänninen; Arul Vadivel; Pauline Bardin; Shumei Zhong; Olli Carpén; Barbara C Vanderhyden; Bernard Thébaud Journal: Stem Cells Date: 2022-05-27 Impact factor: 5.845
Authors: Marta Tellez-Gabriel; Xavier Tekpli; Trine M Reine; Beate Hegge; Stephanie R Nielsen; Meng Chen; Line Moi; Lisa Svartdal Normann; Lill-Tove R Busund; George A Calin; Gunhild M Mælandsmo; Maria Perander; Achilleas D Theocharis; Svein O Kolset; Erik Knutsen Journal: Front Oncol Date: 2022-04-14 Impact factor: 5.738