PMID- 31872544
OWN - NLM
STAT- MEDLINE
DCOM- 20200722
LR  - 20200722
IS  - 2326-5205 (Electronic)
IS  - 2326-5191 (Linking)
VI  - 72
IP  - 6
DP  - 2020 Jun
TI  - Promotion of Myofibroblast Differentiation and Tissue Fibrosis by the Leukotriene 
      B(4) -Leukotriene B(4) Receptor Axis in Systemic Sclerosis.
PG  - 1013-1025
LID - 10.1002/art.41192 [doi]
AB  - OBJECTIVE: To investigate the role of the inflammatory lipid mediator leukotriene 
      B(4) (LTB(4) ) and its receptor, BLT1, in the development and progression of 
      systemic sclerosis (SSc). METHODS: Serum levels of LTB(4) were compared in 64 
      patients with SSc and 80 healthy controls. Skin and lung tissue sections from 
      patients with SSc and healthy donors were immunostained for leukotriene A(4) 
      hydrolase (LTA(4) H), the critical enzyme for LTB(4) synthesis, and BLT1, in 
      combination with different cell markers. In mouse models of SSc using bleomycin 
      or angiotensin II challenge or immunization with the DNA topoisomerase I, genetic 
      or pharmacologic interruption of the LTB(4) -BLT1 axis in mice was carried out to 
      assess its effects on systemic disease features and myofibroblast markers. 
      Immunoblotting was performed to examine the signaling pathway in fibroblasts and 
      endothelial cells following stimulation with LTB(4) or with serum from SSc 
      patients. RESULTS: Serum LTB(4) levels were 44.93% higher in patients with SSc 
      than in matched healthy controls (mean +/- SD 220.3 +/- 74.75 pg/ml versus 152.0 +/- 
      68.05 pg/ml; P < 0.0001), and this was associated with the patient subsets of 
      SSc-associated interstitial lung disease and diffuse cutaneous SSc. Levels of 
      LTA(4) H and BLT1 were increased in lesional areas of the skin and lungs of SSc 
      patients, and both were abundant in myofibroblasts and endothelial cells. 
      Interruption of the LTB(4) -BLT1 axis in mouse models of SSc significantly 
      mitigated dermal and pulmonary fibrosis, with 54.00% and 52.65% fewer alpha-smooth 
      muscle actin-positive myofibroblasts accumulating in the skin and lungs of mice, 
      respectively, after bleomycin challenge. Immunoblotting of cultures with 
      recombinant LTB(4) -stimulated fibroblasts and endothelial cells or with serum 
      from SSc patients showed that fibroblast-myofibroblast and 
      endothelial-mesenchymal transitions were promoted via BLT1, and that this was 
      dependent on activation of the phosphatidylinositol 3-kinase 
      (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway but independent of the 
      release of transforming growth factor beta (TGFbeta) by fibroblasts or endothelial 
      cells. CONCLUSION: The LTB(4) -BLT1 axis may contribute to fibrosis in SSc by 
      directly promoting myofibroblast differentiation via the PI3K/Akt/mTOR pathway, 
      and this appears to operate independently of autocrine secretion of TGFbeta.
CI  - (c) 2019, American College of Rheumatology.
FAU - Liang, Minrui
AU  - Liang M
AUID- ORCID: 0000-0002-7650-1237
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - Lv, Jiaoyan
AU  - Lv J
AD  - Fudan University, Shanghai, China, and Tsinghua University School of Medicine, 
      Beijing, China.
FAU - Jiang, Zhixing
AU  - Jiang Z
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - He, Hang
AU  - He H
AD  - Fudan University, Shanghai, China.
FAU - Chen, Chen
AU  - Chen C
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - Xiong, Yinluo
AU  - Xiong Y
AD  - Fudan University, Shanghai, China.
FAU - Zhu, Xiaoxia
AU  - Zhu X
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - Xue, Yu
AU  - Xue Y
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - Yu, Yiyun
AU  - Yu Y
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - Yang, Sen
AU  - Yang S
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - Wang, Lingbiao
AU  - Wang L
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - Li, Wenjing
AU  - Li W
AD  - Fudan University, Shanghai, China.
FAU - Guan, Ming
AU  - Guan M
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - Wan, Weiguo
AU  - Wan W
AD  - Huashan Hospital and Fudan University, Shanghai, China.
FAU - He, Rui
AU  - He R
AD  - Fudan University, Shanghai, China.
FAU - Zou, Hejian
AU  - Zou H
AD  - Huashan Hospital and Fudan University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200430
PL  - United States
TA  - Arthritis Rheumatol
JT  - Arthritis & rheumatology (Hoboken, N.J.)
JID - 101623795
RN  - 0 (LTB4R protein, human)
RN  - 0 (Receptors, Leukotriene B4)
RN  - 1HGW4DR56D (Leukotriene B4)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
SB  - IM
MH  - Animals
MH  - Case-Control Studies
MH  - Cell Differentiation
MH  - Disease Models, Animal
MH  - Fibrosis
MH  - Humans
MH  - Leukotriene B4/*blood
MH  - Lung/*pathology
MH  - Mice
MH  - Myofibroblasts/metabolism
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Receptors, Leukotriene B4/*blood
MH  - Scleroderma, Systemic/*blood
MH  - Signal Transduction
MH  - Skin/*pathology
EDAT- 2019/12/25 06:00
MHDA- 2020/07/23 06:00
CRDT- 2019/12/25 06:00
PHST- 2019/04/07 00:00 [received]
PHST- 2019/12/17 00:00 [accepted]
PHST- 2019/12/25 06:00 [pubmed]
PHST- 2020/07/23 06:00 [medline]
PHST- 2019/12/25 06:00 [entrez]
AID - 10.1002/art.41192 [doi]
PST - ppublish
SO  - Arthritis Rheumatol. 2020 Jun;72(6):1013-1025. doi: 10.1002/art.41192. Epub 2020 
      Apr 30.