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Unraveling the Role of Endoplasmic Reticulum Stress in Idiopathic Pulmonary Fibrosis (IPF)

dc.creatorBurman, Ankita
dc.description.abstractEndoplasmic reticulum (ER) stress in type II AECs has been associated with pathogenesis of IPF; however, factors inducing ER stress and downstream mechanisms through which ER stress impacts phenotype of type II AECs are not well-understood. We identified localized hypoxia in type II AECs in a repetitive bleomycin-induced lung fibrosis mouse model as a potential mechanism explaining ER stress. We found that C/EBP homologous protein (CHOP), a downstream effector in the ER stress pathway, increases apoptosis of type II AECs and augments fibrosis in 3 separate mouse models. In vitro studies in mouse lung epithelial (MLE12) cells showed that the unfolded protein response (UPR) pathways Inositol-Requiring Enzyme 1α (IRE1α)/X-box Binding Protein 1 (XBP1) and PKR-like ER kinase (PERK)/Activating Transcription Factor 4 (ATF4) regulate CHOP in type II AECs in hypoxia. CHOP regulates hypoxia-induced apoptosis of type II AECs through several pro-apoptotic downstream mediators. On investigating the role of Hypoxia-Inducible Factor (HIF), we found that while epithelial HIF signaling did not affect lung fibrosis after single dose bleomycin treatment or bleomycin treatment followed by exposure to hypoxia, it was important in exacerbation of fibrosis after repetitive bleomycin injury in mice. In human IPF samples, we found prominent expression of both CHOP and markers of hypoxia in type II AECs, supporting the idea of hypoxia-induced ER stress in IPF.
dc.subjectER stress
dc.subjectPulmonary. Fibrosis
dc.titleUnraveling the Role of Endoplasmic Reticulum Stress in Idiopathic Pulmonary Fibrosis (IPF)
dc.contributor.committeeMemberTimothy S. Blackwell
dc.contributor.committeeMemberMark deCaestecker
dc.contributor.committeeMemberVolker Haase
dc.type.materialtext and Developmental Biology University
dc.contributor.committeeChairChin Chiang

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