title: Cell stress induces upregulation of osteopontin via the ERK pathway in type II alveolar epithelial cells.
abstract: Osteopontin (OPN) is a multifunctional protein that plays important roles in cell growth, differentiation, migration and tissue fibrosis. In human idiopathic pulmonary fibrosis and murine bleomycin-induced lung fibrosis, OPN is upregulated in type II alveolar epithelial cells (AEC II). However, the mechanism of OPN induction in AEC II is not fully understood. In this study, we demonstrate the molecular mechanism of OPN induction in AEC II and elucidate the functions of OPN in AEC II and lung fibroblasts. Human lung adenocarcinoma cells (A549) and mouse alveolar epithelial cells (MLE12), used as type II alveolar epithelial cell lines for in vitro assays, and human pulmonary alveolar epithelial cells (HPAEpiC) were treated with either bleomycin, doxorubicin or tunicamycin. The mechanism of OPN induction in these cells and its function as a pro-fibrotic cytokine on A549 and lung fibroblasts were analyzed. The DNA damaging reagents bleomycin and doxorubicin were found to induce OPN expression in A549, MLE12 and HPAEpiC. OPN expression was induced via activation of the extracellular signal-regulated protein kinase (ERK)-dependent signaling pathway in A549 and MLE12. The endoplasmic reticulum (ER) stress-inducing reagent tunicamycin induced OPN mRNA expression in A549, MLE12 and HPAEpiC, and OPN mRNA expression was induced via activation of the ERK-dependent signaling pathway in A549 and MLE12. Another ER stress-inducing reagent thapsigargin induced the expression of OPN mRNA as well as the subsequent production of OPN in A549 and MLE12. Furthermore, OPN promoted the proliferation of A549 and the migration of normal human lung fibroblasts. Inhibition of OPN by small interference RNA or neutralizing antibody suppressed both of these responses. The results of this study suggest that cell stress induces the upregulation of OPN in AEC II by signaling through the ERK pathway, and that upregulated OPN may play a role in fibrogenesis of the lung.
authors: Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Aki
authors: A
authors: Kato
authors: Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Takafumi
authors: T
authors: Okura
authors: Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Chizuru
authors: C
authors: Hamada
authors: Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Seigo
authors: S
authors: Miyoshi
authors: Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Hitoshi
authors: H
authors: Katayama
authors: Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Jitsuo
authors: J
authors: Higaki
authors: Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Ryoji
authors: R
authors: Ito
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics*; D011650:Pulmonary Alveoli / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D012333:RNA, Messenger; D053495:Osteopontin; D001761:Bleomycin; D014415:Tunicamycin; D019284:Thapsigargin; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases