Laminin alpha 1 is a genetic modifier of TGF-beta 1-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-beta 1) was expressed in the lungs of 10 different inbred mouse strains. Surprisingly, the extent of TGF-beta 1- 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 alpha 1 (Lama1) as a genetic modifier for susceptibility to IPF. Subsequent studies demonstrated that Lamal 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, Lamal mRNA expression was significantly increased in lung tissue obtained from IPF patients. These studies identify Lama1 as the genetic modifier of TGF-beta 1 effector responses that significantly affects the development of pulmonary fibrosis.