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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.
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Research Article Pulmonology

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

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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

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Figure 1

Identification of Lama1 as a genetic modifier of TGF-β–stimulated pulmonary fibrosis.

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Identification of Lama1 as a genetic modifier of TGF-β–stimulated pulmon...
Lungs from 6- to 8-week-old WT and TGF-β1–Tg mice on the noted genetic backgrounds were evaluated after the mice were given doxycycline in drinking water for 14 days of to induce Tg. (A) Mallory trichrome evaluation (left panel) and total collagen content measured by Sircol collagen assay (right panel) of lungs from WT and TGF-β1 Tg mice on C57BL/6J (C57) and BALB/cJ (BALB/c) backgrounds. Scale bars: 25 μm. (B) Levels of collagen in lungs from WT and Tg mice on 10 different background strains were measured by Sircol evaluations (n = 7 for each). (C) Illustration of haplotype blocks of Lama1, Wisp1, and Hba-a1. The haplotype of each gene is represented by a colored block, and is presented in the same order as the phenotypic data shown in B. (D) Kinetic evaluation (using qRT-PCR) of the levels of mRNA encoding Lama1 in lungs from WT and TGF-β1 Tg mice on C57 and BALB/c backgrounds at various time points after transgene induction with doxycycline (DOX). (E) Expression of Lama1 mRNA in the lungs of bleomycin-challenged C57 and BALB/c mice. The histology shown in A is representative of at least 5 mice per each group. The values in A, B, D, and E represent mean ± SEM of a minimum number of 5 mice in each group. Post-Bleo, days after bleomycin challenge. *P < 0.05. **P < 0.01. #P < 0.001.

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