Chest
Original ResearchCritical CareLumican Regulates Ventilation-Induced Epithelial-Mesenchymal Transition Through Extracelluar Signal-Regulated Kinase Pathway
Section snippets
Generation and Maintenance of Lumican-Deficient Mice
Male C57BL/6 (either wild-type or lumican deficient) mice aged 3 months and weighing between 25 and 30 g, were obtained from Chang Gung University Laboratory Animal Center (Taoyuan, Taiwan). Lumican-null mice were generated by targeted gene disruption as previously described.13, 21 All procedures for handling mice conformed to Association of Research for Vision and Ophthalmology guidelines. Statements for the use of animals in research were approved by the Institutional Animal Care and Use
Reduction of VILI in Lumican-Deficient Mice
We measured lung EBD and wet weight-to-dry weight ratio to determine the effects of mechanical ventilation on changes of microvascular permeability and lung water content in VILI (Figs 1A, 1B). MPO assay was used to quantitate total lung neutrophils (Fig 1C). We measured MDA level, which is an aldehydic secondary product of lipid peroxidation used as a marker of oxidative stress9 and TGF-β1 and MIP-2 production, to determine the level of oxidant stress and chemoattractants associated with VILI (
Discussion
High Vts in normal animals have been used to mimic the overdistension of the less-injured and, thus, more-compliant areas of lung found in ARDS. Previous studies demonstrated that hyperexpansion of the lung was the cause of noncardiogenic pulmonary edema in VILI.1, 5, 22, 23 A previous study of an acid-induced lung injury model in mice showed that 2 h of mechanical stretch induced lung fibrogenesis.2 Our previous study of hyaluronan synthase knockout mice showed that 5 h of high Vt mechanical
Conclusions
By using an in vivo mouse model of ARDS, this study demonstrated that high Vt mechanical VILI and EMT are associated with activation of ERK1/2 and the production of MIP-2, TGF-β1, and MDA. This process partly depends on the activation of lumican. Knowledge of the effect of mechanical forces on lumican allows clarification of the pathophysiologic mechanisms regulating the fibroproliferative phase of ARDS that may progress to irreversible pulmonary fibrosis and the need for long-term ventilator
Acknowledgments
Author contributions: Drs Li and Yang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Dr Li: contributed to the coordination of the study and review of the manuscript.
Dr Chu: contributed to the coordination of the study and review of the manuscript.
Dr Hung: contributed to the coordination of the study and review of the manuscript.
Dr Kao: contributed to the coordination of the study and review of the
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Cited by (28)
Epithelial-to-mesenchymal transition and invadopodia markers in breast cancer: Lumican a key regulator
2020, Seminars in Cancer BiologyCitation Excerpt :In conclusion, the results taken together indicate that lumican was upregulated before EMT of the LECs and that loss of lumican attenuates injury-induced EMT of LECs [115]. Another case where lumican is reported to regulate EMT is the ventilation-induced EMT through extracellular signal-regulated kinase pathway [116]. In acute lung injury, mechanical ventilation is used in patients, since it damages pulmonary epithelial cells through production of inflammatory cytokines and excess deposition of lumican.
Potential role of M2 macrophage polarization in ventilator-induced lung fibrosis
2019, International ImmunopharmacologyCitation Excerpt :After confirming depth of anesthesia by absence of response to paw compression, the neck skin of mice were cut, blunt dissection, expose the trachea; mice were then subjected to endotracheal intubation by using a 22G Teflon catheter and the trachea hold with catheter were ligated to prevent air leaks. Mice in model groups were then mechanically ventilated with a small animal ventilator ((55–7040, VentElite; Harvard Apparatus, Holliston, MA, US) for 4 h using VT of 20 mL/kg plus 0 cm H2O positive end-expiratory pressure (PEEP) and fraction of inspiration O2(FiO2) 0.4, respiratory rate 80 breaths/min, inspiratory-expiratory ratio 1:1 [11,12]. During the ventilation period, mice were given pentobarbitone (50 mg/kg) as needed; the cocuronium besylate (0.6 mg/kg, H20130486; MSD Performance Products, Kenilworth, NJ, US) was intraperitonealy administered once per hour to achieve muscle relaxation.
MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model
2019, Molecular Therapy Nucleic AcidsCitation Excerpt :The proliferation and accumulation of fibroblasts are considered to be vital in the development of pulmonary fibrosis diseases.3 A large proportion of data implicates that epithelial cells undergoing the process of epithelial-mesenchymal transition (EMT) is one source of fibroblasts.4,5 During EMT, epithelial cells gradually lose their epithelial characteristics and transform into a mesenchymal-like cell phenotype, which begins to synthesize the components of ECM, such as collagen I and fibronectin.
Complex roles of TGF-b signaling pathways in lung development and bronchopulmonary dysplasia
2023, American Journal of Physiology - Lung Cellular and Molecular Physiology
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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).