Laminin α1 is a genetic modifier of TGF-β1–stimulated pulmonary fibrosis
Chang-Min Lee, … , Chun Geun Lee, Jack A. Elias
Chang-Min Lee, … , Chun Geun Lee, Jack A. Elias
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e99574. https://doi.org/10.1172/jci.insight.99574.
View: Text | PDF
Research Article Pulmonology

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

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.

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

×

Figure 3

Lama1 plays an essential role in TGF-β–stimulated pulmonary fibrosis.

Options: View larger image (or click on image) Download as PowerPoint
Lama1 plays an essential role in TGF-β–stimulated pulmonary fibrosis. Lu...
Lungs from 8-week-old WT and TGF-β1 Tg mice were evaluated after 2 weeks of Tg induction by doxycycline in drinking water. (A) Histologic evaluation with Mallory trichrome staining (left) and evaluation of lung collagen content with Sircol assays (right) comparing WT and Tg lungs from mice treated with control scrambled siRNA and Lama1 siRNA. (B) qRT-PCR evaluation of the levels of mRNA encoding extracellular matrix proteins (collagen type1 alpha1 [Col1a1], Col3a1, and fibronectin [FiN]) in lungs from WT and Tg mice treated with control scrambled siRNA or Lama1 siRNA. (C) Representative fluorescence double-label IHC evaluation of α–smooth muscle actin (α-SMA, red), CC10 (green), and nuclei (DAPI, blue) in lungs from WT and TGF-β1 Tg mice treated with scrambled control siRNA or Lama1 siRNA (left panels). Double-label IHC evaluation of α-SMA (green), myosin (red), and nuclei (DAPI, blue) in lungs from TGF-β1 Tg mice treated with scrambled siRNA control or Lama1 siRNA (right panels). (D) α-SMA IHC staining of the lungs of TGF-β1 Tg mice with scrambled siRNA or Lama1 siRNA silencing. Arrows indicate positively stained cells in the interstitial area in the lungs of C57 TGF-β1 Tg mice. A (left) and C are representative of evaluations in a minimum of 3 mice. The values in A and B represent mean ± SEM of evaluations in a minimum of 5 mice each group. *P < 0.05, **P < 0.01. Scale bars: 100 μm (A); 25 μm (C and D).