Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DBR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-κB activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro BDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DBR1. The DBR1 expression level was significantly higher hi fibroblasts from IPF patients, and the predominant isoform was DDA1b. In EPF patients, DDA1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-κB nuclear translocation. Suppression of DBR1 expression in fibroblasts by siRNA abolished these effects, and an NF-κB inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DBR1 up-regulation may occur in other fibroproliferative lung diseases as well. Copyright © American Society for Investigative Pathology.