Idiopathic pulmonary fibrosis (IPF) is an irreversible lethal interstitial lung disease with an unknown cause, killing about 40,000 people per year. In IPF, lung fibroblasts become abnormally activated during tissue repair process, creating excessive scar tissue and avoiding cell death. The results from this research study suggest that the apoptotic pathway mediated by TRAIL (tumor necrosis factor-related apoptotic-inducing ligand) receptors, death receptors 4 and 5 (DR4 and DR5), is aberrant in IPF in the presence of a polymerized collagen matrix. Compared to control fibroblasts, IPF fibroblasts express lower levels of DR4 and DR5, making them more resistant to TRAIL-mediated apoptosis. Furthermore, our study suggests that DR4 may be regulated by the transcription factor FoxO3a. Previous research has shown FoxO3a to be important in conferring an apoptosis-resistant IPF fibroblast phenotype, and these results further support this idea.