Patterns of alveolar epithelial gene expression linked to ER stress & the unfolded protein response in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is hypothesized to originate from aberrant wound healing responses to alveolar epithelial damage. The presence of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) activation has been demonstrated in both familial and sporadic IPF, suggesting that activation of these pathways is a common feature in affected lung tissue. To better understand the biology of the alveolar epithelium in IPF and identify candidate biomarkers of alveolar epithelial injury, we developed a tunicamycin-driven in vitro cell culture model to identify gene expression patterns associated with ER stress and the UPR. We compared gene expression induced by ER stress in in vitro culture to that observed in lung tissue biopsies and sorted type II alveolar epithelial cells (AEC2) from IPF patients. Multiple genes modulated by ER stress in the cell culture model overlapped with differentially expressed genes in IPF lung biopsies and AEC2s. One such gene was HOPX, a transcription factor involved in the differentiation of alveolar epithelial cells. Reduction of HOPX gene expression in vitro using siRNA resulted in an overlapping pattern of gene expression to that driven by tunicamycin-induced ER stress. A subset of genes induced by ER stress in alveolar epithelium encode soluble secreted proteins that could serve as systemic biomarkers. These biomarkers may be used to monitor the degree of alveolar epithelial stress, its activity relative to disease severity and progression, and the effects of therapeutic interventions on this aspect of IPF pathophysiology.