Year: 2018
Type: article
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.
Source: JCI Insight
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Awards: Pre-Clinical Development of a Novel Anti-YKL-40 Biologic to Treat Severe Asthma, Genetic Factors Controlling Effector Function of TGF-beta in COPD and Fibrosis, GLUT1-dependent glycolysis regulates age-susceptible lung fibrosis, Computational Methods for Identification of Genetic Factors Affecting the Response to Drug Abuse, Chitinase1 as a Biomarker and Therapeutic Target in Scleroderma Lung Disease, Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
OpenAlex ID: W2889875331