Cell survival factors in idiopathic pulmonary fibrosis
R.S. Bridges,1 A.C. Borczuk,2 C.A. Glackin3 & S. Greenberg1,4
Departments of 1Pharmacology, 2Pathology, and 4Medicine, Columbia University, New York, NY,
USA and 3Division of Molecular Medicine, Beckman Research Institute of the City of Hope,
Duarte, CA, USA
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease
characterized by Type II epithelial cell hyperplasia, myofibroblast accumulation and excess
collagen deposition. Its pathogenesis is largely unknown, although oxidative injury is likely to
play a role.
Materials and methods: To identify potential disease-modifying genes, we performed
microdissection of tissue samples from fibroblastic foci and determined gene expression profiling
from extracted RNA. We performed immunohistochemistry to localize expression of 4-hydroxy-
2-nonenal, a product of lipid peroxidation, and various proteins identified by microarray analysis.
Results: We found histologic evidence of ongoing oxidative damage in alveolar macrophages,
Type II epithelial cells and mesenchymal cells. We identified expression of many genes in
fibroblastic foci, including extracellular matrix proteins as well as various proteases, such as
aminopeptidases, which are attractive drug targets. One such protease was required for
proliferation and/or accumulation of myofibroblasts in a mouse model of lung injury. Of the most
highly and consistently up-regulated genes was the basic helix-loop-helix transcription factor,
Twist-1. Twist-1 was expressed in Type II epithelial cells and myofiboblasts. Using a variety of
complementary approaches, we have found that Twist-1 is an essential regulator of the anti-
apoptotic and pro-proliferative responses in collagen-expressing fibroblasts and myofibroblasts.
Conclusions: We propose that IPF is characterized by ongoing oxidative damage and
inappropriate survival of collagen-producing mesenchymal cells and that Twist-1 is a central
mediator of this pathologic response.