title: Tetraspanin CD151 protects against pulmonary fibrosis by maintaining epithelial integrity.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined.
  
  
  OBJECTIVE
  To investigate the role of tetraspanin CD151 in pulmonary fibrosis.
  
  
  METHODS
  CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wild-type mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF.
  
  
  RESULTS
  A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased α-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF.
  
  
  CONCLUSIONS
  CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.
authors.affiliation: Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsujino
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Takeda
authors.forename: Toru
authors.initials: T
authors.lastname: Arai
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shintani
authors.forename: Ryosaku
authors.initials: R
authors.lastname: Inagaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saiga
authors.forename: Takeo
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tetsumoto
authors.forename: Yingji
authors.initials: Y
authors.lastname: Jin
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ihara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Minami
authors.forename: Mayumi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Izumi
authors.initials: I
authors.lastname: Nagatomo
authors.forename: Koji
authors.initials: K
authors.lastname: Inoue
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.forename: Takashi
authors.initials: T
authors.lastname: Kijima
authors.forename: Mari
authors.initials: M
authors.lastname: Ito
authors.forename: Masanori
authors.initials: M
authors.lastname: Kitaichi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Inoue
authors.forename: Isao
authors.initials: I
authors.lastname: Tachibana
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Meinoshin
authors.initials: M
authors.lastname: Okumura
authors.forename: Martin E
authors.initials: ME
authors.lastname: Hemler
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D008168:Lung / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D051899:Smad2 Protein / Q000378:metabolism; D060185:Tetraspanin 24 / Q000502:physiology*
chemical_list: C554716:Cd151 protein, mouse; D051899:Smad2 Protein; D060185:Tetraspanin 24; D001761:Bleomycin