The Contribution of LTB4/BLT1 Axis to the Progression of Systemic Sclerosis by Regulating Myofibroblast Formation
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- 英文论文题名：The Contribution of LTB4/BLT1 Axis to the Progression of Systemic Sclerosis by Regulating Myofibroblast Formation
- 论文作者：Liang Minrui ; Jiaoyan lv ; Zhixing Jiang ; Yinluo Xiong ; Rui He ; Hejian Zou
- 英文论文作者：Liang Minrui ; Jiaoyan lv ; Zhixing Jiang ; Yinluo Xiong ; Rui He ; Hejian Zou ; Division of Rheumatology ; Huashan Hospital ; Institute of Rheumatology ; Immunology and Allergy ; Fudan University ; Department of Immunology ; School of Basic Medical Sciences ; Fudan University ; Biotherapy Research Center ; Fudan University
- 年：2016
- 作者机构：Division of Rheumatology,Huashan Hospital;Institute of Rheumatology,Immunology and Allergy,Fudan University;Department of Immunology,School of Basic Medical Sciences,Fudan University;Biotherapy Research Center,Fudan University;
- 英文论文关键词：Leukotriene B4(LTB4) ; BLT1 ; systemic sclerosis(SSc) ; interstitial lung disease(ILD)
- 会议召开时间：2016-11-04
- 会议录名称：第十一届全国免疫学学术大会壁报交流集
- 英文会议录名称：Proceedings of 2016 CSI Congress on Immunology
- 语种：英文
- 分类号：R593.2
- 学会代码：IGMD
- 会议名称：第十一届全国免疫学学术大会
- 会议地点：中国安徽合肥
- 主办单位：中国免疫学会
- 学会名称：中国免疫学会
- 页数：2
- 文件大小：1343k
- 原文格式：D
- 会议级别：全国
摘要
Leukotriene B4(LTB4),a lipid mediator of inflammation,plays a key role in the autoimmune and inflammatory diseases via its high affinity receptor BLT1.Myofibroblast is recognized to be critical in the progression of systemic sclerosis(SSc),but the mechanism is still unknown.We aimed to use BLT1-/-mice and BLT1 specific inhibitor to reveal the contribution of LTB4/BLT1 axis to the progression of SSc in a modified SSc-interstitial lung disease(ILD) mouse model by delivering bleomycin(BLM) via an osmotic mini-pump.In the present study,LTB4 was observed to be up-regulated in the plasma of SSc patients.Also,immunohistochemical analysis demonstrated overexpressions of BLT1 and leukotriene A4 hydrolase(LTA4H),the biosynthetic enzyme for LTB4,in both skin and lung tissues of SSc-ILD subjects.In addition,the levels of BLT1 and LTB4 H were also increasedin the skin and lung tissues of SSc-ILD mouse.BLT1-/-mice did not manifest the phenotype of SSc following the BLM treatment in the SSc-ILD mouse model.And the reduction of α-SMA+ myofibroblasts was also found in the skin and lung tissues of BLT1-/-mice following the administration of BLM,compared with those in wide type mice.Furthermore,the addition of LTB4 was observed to promote fibroblast-myofibroblast transition and endothelial-myofibroblast transition in vitro using primary cell culture,which were reversed by BLT1 inhibition.In addition,LTB4 induced phosphorylation of Akt and m TOR in a time dependent manner in fibroblast,also fibroblast-myofibroblast transition induced by LTB4 was blocked by Akt or m TOR inhibitor.However,LTB4 was not shown to stimulate the release of TGF-β1 in fibroblast,and TGF-β receptor antagonist was not shown to inhibit fibroblast-myofibroblast transition.These results uncover a possible role for LTB4/BLT1 driven myofibroblast formation in SSc-ILD pathogenesis and identify a pathway that may be amenable to therapeutic targeting.
Leukotriene B4(LTB4),a lipid mediator of inflammation,plays a key role in the autoimmune and inflammatory diseases via its high affinity receptor BLT1.Myofibroblast is recognized to be critical in the progression of systemic sclerosis(SSc),but the mechanism is still unknown.We aimed to use BLT1-/-mice and BLT1 specific inhibitor to reveal the contribution of LTB4/BLT1 axis to the progression of SSc in a modified SSc-interstitial lung disease(ILD) mouse model by delivering bleomycin(BLM) via an osmotic mini-pump.In the present study,LTB4 was observed to be up-regulated in the plasma of SSc patients.Also,immunohistochemical analysis demonstrated overexpressions of BLT1 and leukotriene A4 hydrolase(LTA4H),the biosynthetic enzyme for LTB4,in both skin and lung tissues of SSc-ILD subjects.In addition,the levels of BLT1 and LTB4 H were also increasedin the skin and lung tissues of SSc-ILD mouse.BLT1-/-mice did not manifest the phenotype of SSc following the BLM treatment in the SSc-ILD mouse model.And the reduction of α-SMA+ myofibroblasts was also found in the skin and lung tissues of BLT1-/-mice following the administration of BLM,compared with those in wide type mice.Furthermore,the addition of LTB4 was observed to promote fibroblast-myofibroblast transition and endothelial-myofibroblast transition in vitro using primary cell culture,which were reversed by BLT1 inhibition.In addition,LTB4 induced phosphorylation of Akt and m TOR in a time dependent manner in fibroblast,also fibroblast-myofibroblast transition induced by LTB4 was blocked by Akt or m TOR inhibitor.However,LTB4 was not shown to stimulate the release of TGF-β1 in fibroblast,and TGF-β receptor antagonist was not shown to inhibit fibroblast-myofibroblast transition.These results uncover a possible role for LTB4/BLT1 driven myofibroblast formation in SSc-ILD pathogenesis and identify a pathway that may be amenable to therapeutic targeting.
Leukotriene B4(LTB4),a lipid mediator of inflammation,plays a key role in the autoimmune and inflammatory diseases via its high affinity receptor BLT1.Myofibroblast is recognized to be critical in the progression of systemic sclerosis(SSc),but the mechanism is still unknown.We aimed to use BLT1-/-mice and BLT1 specific inhibitor to reveal the contribution of LTB4/BLT1 axis to the progression of SSc in a modified SSc-interstitial lung disease(ILD) mouse model by delivering bleomycin(BLM) via an osmotic mini-pump.In the present study,LTB4 was observed to be up-regulated in the plasma of SSc patients.Also,immunohistochemical analysis demonstrated overexpressions of BLT1 and leukotriene A4 hydrolase(LTA4H),the biosynthetic enzyme for LTB4,in both skin and lung tissues of SSc-ILD subjects.In addition,the levels of BLT1 and LTB4 H were also increasedin the skin and lung tissues of SSc-ILD mouse.BLT1-/-mice did not manifest the phenotype of SSc following the BLM treatment in the SSc-ILD mouse model.And the reduction of α-SMA+ myofibroblasts was also found in the skin and lung tissues of BLT1-/-mice following the administration of BLM,compared with those in wide type mice.Furthermore,the addition of LTB4 was observed to promote fibroblast-myofibroblast transition and endothelial-myofibroblast transition in vitro using primary cell culture,which were reversed by BLT1 inhibition.In addition,LTB4 induced phosphorylation of Akt and m TOR in a time dependent manner in fibroblast,also fibroblast-myofibroblast transition induced by LTB4 was blocked by Akt or m TOR inhibitor.However,LTB4 was not shown to stimulate the release of TGF-β1 in fibroblast,and TGF-β receptor antagonist was not shown to inhibit fibroblast-myofibroblast transition.These results uncover a possible role for LTB4/BLT1 driven myofibroblast formation in SSc-ILD pathogenesis and identify a pathway that may be amenable to therapeutic targeting.
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