4-1BB-ASK-1信号通路对矽尘导致肺纤维化的影响
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摘要
目的:探究4-1BB信号通路对矽尘导致肺纤维化的影响。方法:将小鼠按体重分为生理盐水对照组、生理盐水+阻断剂组(1 0mg/kg)、矽尘暴露组组和矽尘暴露+阻断剂组(10mg/kg)。饲养期间检测体重变化并分别于造模后3天、7天、56天处死动物取材,观察各组小鼠炎症和纤维化情况。检测肺门淋巴结T细胞分型情况,肺泡灌洗液中相关细胞因子含量。检测各组小鼠肺组织中循环纤维细胞(Fibrocyte)所占比例及相关趋化因子的表达情况。结果:与生理盐水对照组相比,矽尘暴露组小鼠肺组织4-1:BB mRNA和蛋白表达量增加;ASK-1抑制剂可以有效阻断4-1BB信号通路;与矽尘暴露组相比,矽尘暴露+阻断剂组小鼠肺组织炎症和纤维化程度均减轻,促炎细胞因子(TNF-毡)表达量下降(P<0.05)。矽尘暴露+阻断剂组小鼠肺门淋巴结中Th1、Th17细胞较矽尘暴露组明显减少(P<0.05):肺泡灌洗液中相关细胞(IFN-γ、IL-17A)因子的含量较矽尘暴露组也有明显下降(P<0.05);与矽尘暴露组相比,阻断4-1BB信号通路后调节性T细胞(Treg)的数目下降(P<0.05),肺泡灌洗液中IL-10含量下降(P<0.05)。与对照组相比,矽尘暴露组小鼠肺组织中循环纤维细胞(Fibrocyte)含量明显增加(P<0.05),使用阻断剂可以使肺组织中循环纤维细胞含量降低(P<0.05)。结论:4-1BB信号通路在矽尘导致肺部纤维化进展中起重要作用,阻断该通路可以减轻二氧化硅导致肺部炎症和纤维化。该通路可能成为延缓二氧化硅导致肺部纤维化的靶点之一。
引文
1.Lopes-Pacheco M,Bandeira E,Morales MM.Cell-Based Therapy for Silicosis.Stem Cells Int.2016;2016:5091838.
2.Leung CC,Yu ITS,Chen W.Silicosis.The Lancet.2012;379:2008-18.
3 Bang KM,Mazurek JM,Wood JM,White GE,Hendricks SA,Weston A.Silicosis mortality trends and new exposures to respirable crystalline silica-United States,2001-2010.MMWR Morb Mortal Wkly Rep.2015;64:117-20.
4.Watts TH.TNF/TNFR family members in costimulation of T cell responses.Annual review of immunology.2005;23:23-68.
5.Cannons JL,Choi Y,Watts TH.Role of TNF Receptor-Associated Factor 2 and p38 Mitogen-Activated Protein Kinase Activation During 4-1BB-Dependent Immune Response.The Journal of Immunology.2000;165:6193-204.
6.Lee SW,Salek-Ardakani S,Mittler RS,Croft M.Hypercostimulation through 4-1BB Distorts Homeostasis of Immune Cells.Journal of immunology.2009;182:6753-62.
7.Hammaker D,Firestein G."Go upstream,young man":lessons learned from the p38 saga.Ann Rheum Dis.2010;69:i77-i82.
8.Ma FY,Tesch GH,Nikolic-Paterson DJ.ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney.American journal of physiology Renal physiology.2014;307:F1263-73.
9.Park SJ,Kim HJ,Lee JS,Cho HR,Kwon B.Reverse signaling through the co-stimulatory ligand,CD137L,as a critical mediator of sterile inflammation.Mol Cells.2012;33:533-7.
10.Re SL,Lison D,Huaux F.CD4+T lymphocytes in lung fibrosis:diverse subsets,diverse functions.Journal of leukocyte biology.2013;93:499-510.
2.Leung CC,Yu ITS,Chen W.Silicosis.The Lancet.2012;379:2008-18.
3 Bang KM,Mazurek JM,Wood JM,White GE,Hendricks SA,Weston A.Silicosis mortality trends and new exposures to respirable crystalline silica-United States,2001-2010.MMWR Morb Mortal Wkly Rep.2015;64:117-20.
4.Watts TH.TNF/TNFR family members in costimulation of T cell responses.Annual review of immunology.2005;23:23-68.
5.Cannons JL,Choi Y,Watts TH.Role of TNF Receptor-Associated Factor 2 and p38 Mitogen-Activated Protein Kinase Activation During 4-1BB-Dependent Immune Response.The Journal of Immunology.2000;165:6193-204.
6.Lee SW,Salek-Ardakani S,Mittler RS,Croft M.Hypercostimulation through 4-1BB Distorts Homeostasis of Immune Cells.Journal of immunology.2009;182:6753-62.
7.Hammaker D,Firestein G."Go upstream,young man":lessons learned from the p38 saga.Ann Rheum Dis.2010;69:i77-i82.
8.Ma FY,Tesch GH,Nikolic-Paterson DJ.ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney.American journal of physiology Renal physiology.2014;307:F1263-73.
9.Park SJ,Kim HJ,Lee JS,Cho HR,Kwon B.Reverse signaling through the co-stimulatory ligand,CD137L,as a critical mediator of sterile inflammation.Mol Cells.2012;33:533-7.
10.Re SL,Lison D,Huaux F.CD4+T lymphocytes in lung fibrosis:diverse subsets,diverse functions.Journal of leukocyte biology.2013;93:499-510.