Lumican Regulates Ventilation-Induced Epithelial-Mesenchymal Transition Through Extracelluar Signal-Regulated Kinase Pathway
Lumican Regulates Ventilation-Induced Epithelial-Mesenchymal Transition Through Extracelluar Signal-Regulated Kinase Pathway
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DOI：
10.1378/chest.12-2058
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发表时间：
2013-05-01
期刊：
影响因子：
9.6
通讯作者：
Yang, Cheng-Ta
中科院分区：
文献类型：
--
作者：
Li, Li-Fu;Chu, Pao-Hsien;Yang, Cheng-Ta
背景：机械通气治疗急性肺损伤可通过产生炎性细胞因子和细胞外基质蛋白LUMICAN过度沉积来损伤肺上皮细胞。Lumcan参与了急性肺损伤纤维增生期巨噬细胞炎性蛋白(MIP)-2和转化生长因子-β(1)(1)的信号转导，参与了上皮-间充质转化(EMT)过程。机械通气和肺损伤之间相互作用的调节机制尚不清楚。我们假设大潮气量(V-T)机械牵张引起的肺损伤和EMT可通过细胞外信号调节激酶(ERK)1/2途径调节LUMICA上调MIP-2和TGF-β(1)。方法：3月龄雄性C57BL/6小鼠(野生型或LUMICAN零)，体重25~30g，暴露于低V-T(6mL/kg)或高V-T(30mL/kg)机械通气室内2~8h。结果：高V-T机械通气量增加微血管通透性、微血管通透性、微血管通透性、微血管通透性、微血管通透性和微血管通透性等指标野生型小鼠中性粒细胞内流、自由基、MIP-2和转化生长因子-β(1)蛋白的产生，α-平滑肌肌动蛋白和S100A4/成纤维细胞特异性蛋白-1的阳性染色，Masson三色染色和细胞外胶原，以及Lumcan和ERK1/2的激活。上皮性标记物E-钙粘附素的染色也减少。结论：鲁米肯通过激活ERK1/2通路促进高V-T机械通气所致的肺损伤和EMT。
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-beta(1) (TGF-beta(1)) 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 (V-T) mechanical stretch causes upregulation of lumican that modulates MIP-2 and TGF-beta(1) 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 V-T (6 mL/kg) or high V-T (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 V-T mechanical ventilation increased microvascular permeability, neutrophil influx, production of free radicals, MIP-2 and TGF-beta(1) proteins, positive staining of alpha-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 V-T mechanical ventilation-induced lung injury and EMT through the activation of the ERK1/2 pathway.