title: Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress.
abstract: Expression of mutant surfactant protein C (SFTPC) results in endoplasmic reticulum (ER) stress in type II alveolar epithelial cells (AECs). AECs have been implicated as a source of lung fibroblasts via epithelial-to-mesenchymal transition (EMT); therefore, we investigated whether ER stress contributes to EMT as a possible mechanism for fibrotic remodeling. ER stress was induced by tunicamyin administration or stable expression of mutant (L188Q) SFTPC in type II AEC lines. Both tunicamycin treatment and mutant SFTPC expression induced ER stress and the unfolded protein response. With tunicamycin or mutant SFTPC expression, phase contrast imaging revealed a change to a fibroblast-like appearance. During ER stress, expression of epithelial markers E-cadherin and Zonula occludens-1 decreased while expression of mesenchymal markers S100A4 and α-smooth muscle actin increased. Following induction of ER stress, we found activation of a number of pathways, including MAPK, Smad, β-catenin, and Src kinase. Using specific inhibitors, the combination of a Smad2/3 inhibitor (SB431542) and a Src kinase inhibitor (PP2) blocked EMT with maintenance of epithelial appearance and epithelial marker expression. Similar results were noted with siRNA targeting Smad2 and Src kinase. Together, these studies reveal that induction of ER stress leads to EMT in lung epithelial cells, suggesting possible cross-talk between Smad and Src kinase pathways. Dissecting pathways involved in ER stress-induced EMT may lead to new treatment strategies to limit fibrosis.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Nashville, Tennessee 37232-2650. Electronic address: harikrishna.tanjore@vanderbilt.edu.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Tanjore
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Nashville, Tennessee 37232-2650.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Nashville, Tennessee 37232-2650.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Degryse
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Nashville, Tennessee 37232-2650.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Zoz
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Nashville, Tennessee 37232-2650.
authors.forename: Rasul
authors.initials: R
authors.lastname: Abdolrasulnia
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Nashville, Tennessee 37232-2650; Department of Veterans Affairs Medical Center, Nashville, Tennessee 37232-2650.
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Nashville, Tennessee 37232-2650; Department of Veterans Affairs Medical Center, Nashville, Tennessee 37232-2650; Department of Cell and Developmental Biology, Nashville, Tennessee 37232-2650; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008858:Microscopy, Phase-Contrast / Q000379:methods; D008954:Models, Biological; D009154:Mutation; D010750:Phosphoproteins / Q000096:biosynthesis; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism; D051381:Rats; D014415:Tunicamycin / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein
chemical_list: D015820:Cadherins; D008565:Membrane Proteins; D010750:Phosphoproteins; D037721:Pulmonary Surfactant-Associated Protein C; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D014415:Tunicamycin; D000111:Acetylcysteine