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Laminin α1 is a genetic modifier of TGF-β1-stimulated pulmonary fibrosis

Authors
 Chang-Min Lee  ;  Soo Jung Cho  ;  Won-Kyung Cho  ;  Jin Wook Park  ;  Jae-Hyun Lee  ;  Augustine M. Choi  ;  Ivan O. Rosas  ;  Ming Zheng  ;  Gary Peltz  ;  Chun Geun Lee  ;  Jack A. Elias 
Citation
 JCI INSIGHT, Vol.3(18) : e99574, 2018 
Journal Title
 JCI INSIGHT 
Issue Date
2018
MeSH
Animals ; Cell Proliferation ; Extracellular Matrix Proteins/metabolism ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Idiopathic Pulmonary Fibrosis/genetics* ; Idiopathic Pulmonary Fibrosis/metabolism* ; Idiopathic Pulmonary Fibrosis/pathology ; Laminin/genetics* ; Laminin/metabolism* ; Lung/pathology ; Lung Injury ; Macrophage Activation ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Smad2 Protein/metabolism ; Transforming Growth Factor beta1/metabolism*
Abstract
The pathogenetic mechanisms underlying the pathologic fibrosis in diseases such as idiopathic pulmonary fibrosis (IPF) are poorly understood. To identify genetic factors affecting susceptibility to IPF, we analyzed a murine genetic model of IPF in which a profibrotic cytokine (TGF-β1) was expressed in the lungs of 10 different inbred mouse strains. Surprisingly, the extent of TGF-β1-induced lung fibrosis was highly strain dependent. Haplotype-based computational genetic analysis and gene expression profiling of lung tissue obtained from fibrosis-susceptible and -resistant strains identified laminin α1 (Lama1) as a genetic modifier for susceptibility to IPF. Subsequent studies demonstrated that Lama1 plays an important role in multiple processes that affect the pulmonary response to lung injury and susceptibility to fibrosis, which include: macrophage activation, fibroblast proliferation, myofibroblast transformation, and the production of extracellular matrix. Also, Lama1 mRNA expression was significantly increased in lung tissue obtained from IPF patients. These studies identify Lama1 as the genetic modifier of TGF-β1 effector responses that significantly affects the development of pulmonary fibrosis.
Files in This Item:
T201806243.pdf Download
DOI
10.1172/jci.insight.99574
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jae Hyun(이재현) ORCID logo https://orcid.org/0000-0002-0760-0071
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175165
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