脂多糖致急性肺血管内皮屏障功能失调小鼠FLI-1蛋白表达的变化及其意义

doi:10.12047/j.cjap.6080.2021.040

摘要/Abstract

摘要： 目的: 观察感染性急性肺损伤(ALI)肺血管内皮屏障功能失调小鼠肺组织中弗里德白血病病毒插入位点1(FLI-1)蛋白表达的变化,以探讨FLI-1在感染性ALI肺血管内皮屏障功能失调发生发展中的意义。方法: SPF级雄性ICR小鼠60只,腹腔注射脂多糖(LPS,7.5 mg/kg)复制ALI模型,在给予LPS 0 h、12 h、24 h、48 h后,检测小鼠肺血管内皮屏障通透性和肺湿干重比,ELISA法检测肺泡灌洗液中TNF-α和IL-6含量,Western blot法检测肺组织FLI-1和Src酪氨酸激酶(SRC)蛋白的表达。结果: 与0 h组比较,12 h组、24 h组肺血管内皮屏障通透性分别升高74.3%和162.4%,而48 h组较24 h组降低27.0%(P均＜0.05);与0 h组比较,12 h组、24 h组肺湿干重比分别升高50.1%和122.9%,而48 h组较24 h组降低10.7%(P均＜0.05);与0 h组比较,12 h、24 h肺泡灌洗液IL-6和TNF-α含量均显著升高,而48 h肺泡灌洗液IL-6和TNF-α含量较24 h分别下降28.3%和21.6%(P均＜ 0.05);与0 h组比较,12 h组、24 h组肺组织FLI-1蛋白表达水平分别下调20.4%和56.9%,而48 h组较24 h组上调18.2%(P均＜0.05);与0 h组比较,12 h组、24 h组肺组织SRC蛋白表达水平分别上调76.8%和176.7%,而48 h组较24 h组下调33.4%(P均＜0.05);肺血管内皮屏障通透性与FLI-1蛋白表达水平呈显著负相关(r= -0.8992,P＜0.01),而与SRC蛋白表达水平呈显著正相关(r=0.8918,P＜0.01),肺组织FLI-1与SRC蛋白表达呈显著负相关(r=-0.8087,P=0.0014)。结论: FLI-1可能参与LPS诱导的急性肺损伤肺血管内皮屏障功能失常过程。

关键词: 脂多糖, 急性肺损伤, FLI-1, 肺血管内皮屏障

Abstract: Objective: To observe changes of Friend leukemia virus integration 1 (FLI-1) protein expression of pulmonary tissue in mice with pulmonary endothelial barrier dysfunction following acute lung injury (ALI) induced by lipopolysaccharide (LPS). Methods: The mouse model of ALI was established by injection of LPS (7.5 mg/kg, i.p. ). At 0 h, 12 h, 24 h and 48 h after LPS injection, pulmonary microvascular endothelial permeability and lung wet/dry weight ratio (W/D) were assessed. The contents of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF) were detected by ELISA method. The protein levels of FLI-1 and Src protein tyrosine kinase (SRC) were analyzed by Western blotting.Results: ①Pulmonary microvascular endothelial permeability at 12 h and 24 h were significantly higher than those of 0 h by 74.3% and 162.4%, respectively, while that of 48 h was lower than that of 24 h by 27.0% (P＜0.05). The W/D at 12 h and 24 h were significantly higher than those of 0 h by 50.1% and 122.9%, respectively, while that of 48 h was lower than that of 24 h by 10.7% (P＜0.05). ②The contents of IL-6 and TNF-α in BALF at 12 h and 24 h were significantly higher than those of 0 h, while those of 48 h were significantly lower than those of 24 h by 28.3% and 21.6% (P＜0.05), respectively. ③The protein level of FLI-1 in lung at 12 h and 24 h were down-regulated than those of 0 h by 20.4% and 56.9%, respectively, while that of 48 h was up-regulated than that of 24 h by 18.2% (P＜0.05). The protein level of SRC in lung at 12 h and 24 h were up-regulated than those of 0 h by 76.8% and 176.7%, respectively, while that of 48 h was down-regulated than that of 24 h by 33.4% (P＜0.05).④Same as the protein level of FLI-1 with the protein level of SRC in lung, pulmonary microvascular endothelial permeability was significantly negative correlated with the protein level of FLI-1 in lung, while it was significantly positive correlated with the protein level of SRC (P＜0.01). Conclusion: FLI-1 participates in the pathological proceeding of pulmonary endothelial barrier dysfunction following ALI induced by LPS.

Key words: lipopolysaccharide, acute lung injury, FLI-1, pulmonary endothelial barrier

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R363.2

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徐立聪, 黄婷婷, 郝家乐, 范小芳, 龚永生, 毛孙忠. 脂多糖致急性肺血管内皮屏障功能失调小鼠FLI-1蛋白表达的变化及其意义[J]. 中国应用生理学杂志, 2021, 37(4): 393-396.

XU Li-cong, HUANG Ting-ting, HAO Jia-le, FAN Xiao-fang, GONG Yong-sheng, MAO Sun-zhong. Changes of FLI-1 protein expression in mice with pulmonary endothelial barrier dysfunction following acute lung injury induced by lipopolysaccharide[J]. CJAP, 2021, 37(4): 393-396.

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参考文献 13

[1] Zhou Y, Li P, Goodwin AJ, et al. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury [J]. Crit Care, 2019, 23(1): 44(1-12).

[2] Park SW, Do HJ, Choi W, et al. Fli-1 promotes proliferation and upregulates NANOGP8 expression in T-lymphocyte leukemia cells [J]. Biochimie, 2020, 168: 1-9.

[3] Looney AP, Han R, Stawski L, et al. Synergistic role of endothelial ERG and FLI1 in mediating pulmonary vascular homeostasis [J]. Am J Respir Cell Mol Biol, 2017, 57(1): 121-131

[4] Dong W, He B, Qian H, Liu Q, et al. RAB26-dependent autophagy protectsadherens junctional integrity in acute lung injury [J]. Autophagy, 2018, 1410(10): 1677-1692.

[5] Lakhanpal GK, Vecchiarelli-Federico LM, Li YJ, et al. The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis [J]. Blood, 2010, 116 (3): 428-436.

[6] Mao SZ, Ye X, Liu G, et al. Resident endothelial cells and endothelial progenitor cells restore endothelial barrier function after inflammatory lung injury [J]. Arterioscler Thromb Vasc Biol, 2015, 35(7): 1635-1644.

[7] Asano Y, Stawski L, Hant F, et al. Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy [J]. Am J Pathol, 2010, 176 (4): 1983-1998.

[8] Stawski L, Marden G, Trojanowska M. The activation of human dermal microvascular cells by Poly(I:C), lipopolysaccharide, imiquimod, and ODN2395 is mediated by the Fli1/FOXO3A pathway [J]. J Immunol, 2018, 200(1): 248-259.

[9] Lee HS, Moon C, Lee HW, et al. Src tyrosine kinases mediate activations of NF-kappaB and integrin signal during lipopolysaccharide-induced acute lung injury [J]. J Immunol, 2007, 179(10): 7001-7011.

[10] Zhong M, Wu W, Kang H, et al. Alveolar stretch activation of endothelial piezo1 protects adherens junctions and lung vascular barrier [J]. Am J Respir Cell Mol Biol, 2020, 62(2): 168-177.

[11] Barabutis N, Verin A, Catravas JD. Regulation of pulmonary endothelial barrier function by kinases [J]. Am J Physiol Lung Cell Mol Physiol, 2016, 311(5): L832-L845.

[12] Wang N, Zhang D, Sun G, et al. Lipopolysaccharide-induced caveolin-1 phosphorylation- dependent increase in transcellular permeability precedes the increase in paracellular permeability [J]. Drug Des Devel Ther, 2015, 9: 4965-4977.

[13] Kim J, Nguyen TTT, Li Y, et al. Contrasting effects of stored allogeneic red blood cells and their supernatants on permeability and inflammatory responses in human pulmonary endothelial cells [J]. Am J Physiol Lung Cell Mol Physiol, 2020, 318(3): L533-L548.

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[1] 赵嘉涵, 贾雨涵, 汤雅婷, 林艺鑫, 王艳蕾. 参麦注射液对肠缺血/再灌注肺损伤大鼠肺组织p38MAPK及凋亡相关基因表达的影响[J]. 中国应用生理学杂志, 2019, 35(1): 65-68.

[2] 黄斌, 邓旺, 王导新. p38丝裂原活化蛋白激酶在大鼠油酸型急性肺损伤中的作用[J]. 中国应用生理学杂志, 2017, 33(4): 334-339.

[3] 罗鹏, 周振兴. 血必净对大鼠急性肺损伤的保护作用[J]. 中国应用生理学杂志, 2017, 33(2): 132-135.

[4] 蒋伟, 张弦, 周爱玲. TLR₄/P38/JNK信号通路在海马神经元凋亡中的作用[J]. 中国应用生理学杂志, 2016, 32(6): 571-576.

[5] 宋英, 许西西, 丁维, 茅东升. 神经节苷脂对脂多糖损伤大鼠嗜铬细胞瘤细胞的保护作用[J]. 中国应用生理学杂志, 2016, 32(4): 310-313.

[6] 詹光杰, 肖本见, 杨年安. 延龄草对LPS诱导大鼠肝损伤的保护作用及机制[J]. 中国应用生理学杂志, 2016, 32(4): 373-377.

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脂多糖致急性肺血管内皮屏障功能失调小鼠FLI-1蛋白表达的变化及其意义

Changes of FLI-1 protein expression in mice with pulmonary endothelial barrier dysfunction following acute lung injury induced by lipopolysaccharide

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[1]	Zhou Y, Li P, Goodwin AJ, et al. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury [J]. Crit Care, 2019, 23(1): 44(1-12).
[2]	Park SW, Do HJ, Choi W, et al. Fli-1 promotes proliferation and upregulates NANOGP8 expression in T-lymphocyte leukemia cells [J]. Biochimie, 2020, 168: 1-9.
[3]	Looney AP, Han R, Stawski L, et al. Synergistic role of endothelial ERG and FLI1 in mediating pulmonary vascular homeostasis [J]. Am J Respir Cell Mol Biol, 2017, 57(1): 121-131
[4]	Dong W, He B, Qian H, Liu Q, et al. RAB26-dependent autophagy protectsadherens junctional integrity in acute lung injury [J]. Autophagy, 2018, 1410(10): 1677-1692.
[5]	Lakhanpal GK, Vecchiarelli-Federico LM, Li YJ, et al. The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis [J]. Blood, 2010, 116 (3): 428-436.
[6]	Mao SZ, Ye X, Liu G, et al. Resident endothelial cells and endothelial progenitor cells restore endothelial barrier function after inflammatory lung injury [J]. Arterioscler Thromb Vasc Biol, 2015, 35(7): 1635-1644.
[7]	Asano Y, Stawski L, Hant F, et al. Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy [J]. Am J Pathol, 2010, 176 (4): 1983-1998.
[8]	Stawski L, Marden G, Trojanowska M. The activation of human dermal microvascular cells by Poly(I:C), lipopolysaccharide, imiquimod, and ODN2395 is mediated by the Fli1/FOXO3A pathway [J]. J Immunol, 2018, 200(1): 248-259.
[9]	Lee HS, Moon C, Lee HW, et al. Src tyrosine kinases mediate activations of NF-kappaB and integrin signal during lipopolysaccharide-induced acute lung injury [J]. J Immunol, 2007, 179(10): 7001-7011.
[10]	Zhong M, Wu W, Kang H, et al. Alveolar stretch activation of endothelial piezo1 protects adherens junctions and lung vascular barrier [J]. Am J Respir Cell Mol Biol, 2020, 62(2): 168-177.
[11]	Barabutis N, Verin A, Catravas JD. Regulation of pulmonary endothelial barrier function by kinases [J]. Am J Physiol Lung Cell Mol Physiol, 2016, 311(5): L832-L845.
[12]	Wang N, Zhang D, Sun G, et al. Lipopolysaccharide-induced caveolin-1 phosphorylation- dependent increase in transcellular permeability precedes the increase in paracellular permeability [J]. Drug Des Devel Ther, 2015, 9: 4965-4977.
[13]	Kim J, Nguyen TTT, Li Y, et al. Contrasting effects of stored allogeneic red blood cells and their supernatants on permeability and inflammatory responses in human pulmonary endothelial cells [J]. Am J Physiol Lung Cell Mol Physiol, 2020, 318(3): L533-L548.

[1]	赵嘉涵, 贾雨涵, 汤雅婷, 林艺鑫, 王艳蕾. 参麦注射液对肠缺血/再灌注肺损伤大鼠肺组织p38MAPK及凋亡相关基因表达的影响[J]. 中国应用生理学杂志, 2019, 35(1): 65-68.
[2]	黄斌, 邓旺, 王导新. p38丝裂原活化蛋白激酶在大鼠油酸型急性肺损伤中的作用[J]. 中国应用生理学杂志, 2017, 33(4): 334-339.
[3]	罗鹏, 周振兴. 血必净对大鼠急性肺损伤的保护作用[J]. 中国应用生理学杂志, 2017, 33(2): 132-135.
[4]	蒋伟, 张弦, 周爱玲. TLR₄/P38/JNK信号通路在海马神经元凋亡中的作用[J]. 中国应用生理学杂志, 2016, 32(6): 571-576.
[5]	宋英, 许西西, 丁维, 茅东升. 神经节苷脂对脂多糖损伤大鼠嗜铬细胞瘤细胞的保护作用[J]. 中国应用生理学杂志, 2016, 32(4): 310-313.
[6]	詹光杰, 肖本见, 杨年安. 延龄草对LPS诱导大鼠肝损伤的保护作用及机制[J]. 中国应用生理学杂志, 2016, 32(4): 373-377.