title: Increased ectodomain shedding of cell adhesion molecule 1 as a cause of type II alveolar epithelial cell apoptosis in patients with idiopathic interstitial pneumonia.
abstract: BACKGROUND
  Lung alveolar epithelial cell (AEC) apoptosis has attracted attention as an early pathogenic event in the development of idiopathic interstitial pneumonia (IIP); however, the causative mechanism remains unclear. Cell adhesion molecule 1 (CADM1) is an AEC adhesion molecule in the immunoglobulin superfamily. It generates a membrane-associated C-terminal fragment, αCTF, through protease-mediated ectodomain shedding, termed α-shedding. Increased CADM1 α-shedding contributes to AEC apoptosis in emphysematous lungs.
  
  
  METHODS
  Formalin-fixed, paraffin-embedded lung lobes (n = 39) from 36 autopsied patients with IIP were classified as acute IIP (n = 10), fibrosing-type nonspecific IIP (f-NSIP, n = 10), cryptogenic organizing IIP (n = 9), and usual IIP (n = 10). CADM1 expression in the lung sections was examined by western blotting and compared with control lungs (n = 10). The rate of CADM1 α-shedding was calculated as the relative amount of αCTF to full-length CADM1, and the full-length CADM1 level was estimated per epithelial cell by normalization to cytokeratin 7, a lung epithelial marker. Apoptotic AECs were detected by immunohistochemistry for single-stranded DNA (ssDNA). NCI-H441 and A549 human lung epithelial cells were transfected with small interfering RNA (siRNA) to silence CADM1 expression and analyzed by terminal nucleotide nick end labeling assays.
  
  
  RESULTS
  The rate of CADM1 α-shedding was higher in all IIP subtypes than in the control (P ≤ 0.019), and the full-length CADM1 level was lower in f-NSIP (P = 0.007). The α-shedding rate and full-length CADM1 level were correlated with each other (P = 0.015) and with the proportion of ssDNA-positive AECs (P ≤ 0.024). NCI-H441 cells transfected with siRNA exhibited a 61 % lower rate of expression of full-length CADM1 and a 17-fold increased proportion of apoptotic cells. Similar results were obtained with A549 cells.
  
  
  CONCLUSIONS
  CADM1 α-shedding appeared to be increased in all four IIP subtypes and consequently contributed to AEC apoptosis by decreasing the full-length CADM1 level. This mechanism particularly impacted f-NSIP. The molecular mechanism causing AEC apoptosis may be similar between IIP and emphysema.
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Yoneshige
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan.
authors.forename: Man
authors.initials: M
authors.lastname: Hagiyama
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mimae
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Morihito
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Enoki
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan. aito@med.kindai.ac.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056809:Alveolar Epithelial Cells / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000502:physiology*; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias / Q000175:diagnosis / Q000378:metabolism*; D007136:Immunoglobulins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins