title: Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial-mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci (FF) represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: (1) from resident fibroblasts, (2) from bone marrow-derived progenitors of fibroblasts, and (3) from alveolar epithelial cells that have undergone epithelial-mesenchymal transition (EMT). We found that FF dissociated capillary vessels from the alveolar epithelia, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100 μm below the alveolar epithelia. Furthermore, the alveolar epithelial cells covering the FF exhibited a partial EMT phenotype. In addition, normal human alveolar epithelial cells in vitro underwent dynamic EMT in response to transforming growth factor-β signaling within 72 h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the alveolar epithelia and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned alveolar epithelia located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-β signaling, which can suppress EMT of the alveolar epithelial cells in vitro, is a potential strategy for treating IPF.
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sumi
authors.affiliation: Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Miyajima
authors.affiliation: Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Taijiro
authors.initials: T
authors.lastname: Mishina
authors.affiliation: Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
authors.affiliation: Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Otsuka
authors.affiliation: Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Department of Pathology, Jichi Medical University School of Medicine, Tochigi, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.affiliation: Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakuma
mesh_terms: D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology*; D011652:Pulmonary Circulation; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D014746:Vimentin; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1