SESSION TYPE: ILD Posters
PRESENTED ON: Wednesday, October 24, 2012 at 01:30 PM - 02:30 PM
PURPOSE: Among the various interstitial lung diseases, idiopathic pulmonary fibrosis (IPF) is the most common, devastating, and fatal. A progressive condition of unknown etiology with a clear predilection for the elderly, IPF almost invariably ends in respiratory failure within five years of diagnosis. The limited understanding of IPF pathogenesis precludes the ability to provide effective treatment options. Evidence suggests that endoplasmic reticulum (ER) stress, protein misfolding, and the subsequent unfolded protein response (UPR) may represent a mechanism in the development of pulmonary fibrosis, as part of a dysfunctional repair process following lung injury. We therefore investigate whether the aging epithelium is more susceptible to ER stress and activation of the UPR.
METHODS: Using a murine model of pulmonary fibrosis and ER stress, we conduct in vivo and in vitro studies in young and aged C57Bl6 mice. Intrapulmonary tunicamycin is administered to induce ER stress. Protein expression of key components of the ER stress/UPR system is examined. Hydroxyproline assay and histology evaluate for the development of fibrosis.
RESULTS: In mouse whole lung and primary type 2 alveolar epithelial cells, tunicamycin reliably induces ER stress. Basal levels of protein chaperones are lower in naïve aged mice as compared to naïve young mice. Aged mice also display less BiP increase following ER stress. Basal levels of pro-apoptotic factors are higher in naïve aged mice and increase further following ER stress. Aged mice develop significantly more fibrosis in response to bleomycin as compared to their younger counterparts.
CONCLUSIONS: In mouse lung, aging alters the unfolded protein response to ER stress. Augmented lung fibrosis is seen in aging, which may be in part due to an altered ER stress/UPR pathway.
CLINICAL IMPLICATIONS: With enhanced understanding of the molecular and cellular aspects of pulmonary aging, and in particular the interaction between aging, pulmonary fibrosis, and ER stress, the ultimate goal is to develop effective therapies for, and thereby reduce mortality from, IPF.
DISCLOSURE: The following authors have nothing to disclose: Jessica Chia, Kenneth Schmader, Paul Noble
No Product/Research Disclosure InformationDuke University Medical Center, Durham, NC