%0 Journal Article %1 Tsujino2012 %A Tsujino, Kazuyuki %A Takeda, Yoshito %A Arai, Toru %A Shintani, Yasushi %A Inagaki, Ryosaku %A Saiga, Hiroyuki %A Iwasaki, Takeo %A Tetsumoto, Satoshi %A Jin, Yingji %A Ihara, Shoichi %A Minami, Toshiyuki %A Suzuki, Mayumi %A Nagatomo, Izumi %A Inoue, Koji %A Kida, Hiroshi %A Kijima, Takashi %A Ito, Mari %A Kitaichi, Masanori %A Inoue, Yoshikazu %A Tachibana, Isao %A Takeda, Kiyoshi %A Okumura, Meinoshin %A Hemler, Martin E. %A Kumanogoh, Atsushi %D 2012 %J Am J Respir Crit Care Med %K exosome gene-expression bos %N 2 %P 170--180 %R 10.1164/rccm.201201-0117OC %T Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity. %U http://dx.doi.org/10.1164/rccm.201201-0117OC %V 186 %X Rationale: 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. Objectives: 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. Measurements and Main 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.

@article{Tsujino2012, abstract = {Rationale: 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. Objectives: 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. Measurements and Main 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.}, added-at = {2012-07-20T00:11:21.000+0200}, author = {Tsujino, Kazuyuki and Takeda, Yoshito and Arai, Toru and Shintani, Yasushi and Inagaki, Ryosaku and Saiga, Hiroyuki and Iwasaki, Takeo and Tetsumoto, Satoshi and Jin, Yingji and Ihara, Shoichi and Minami, Toshiyuki and Suzuki, Mayumi and Nagatomo, Izumi and Inoue, Koji and Kida, Hiroshi and Kijima, Takashi and Ito, Mari and Kitaichi, Masanori and Inoue, Yoshikazu and Tachibana, Isao and Takeda, Kiyoshi and Okumura, Meinoshin and Hemler, Martin E. and Kumanogoh, Atsushi}, biburl = {https://www.bibsonomy.org/bibtex/245dc4ff6e3995beb04430a5ba1566ea0/aorchid}, description = {see page 63 for comments in notebook 00002}, doi = {10.1164/rccm.201201-0117OC}, file = {:allorejection/AmJRespirCritCareMed.186.170.pdf:PDF}, groups = {public}, institution = {Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. yoshito@imed3.med.osaka-u.ac.jp.}, interhash = {bc232391b5bb8f1644245867e5621667}, intrahash = {45dc4ff6e3995beb04430a5ba1566ea0}, journal = {Am J Respir Crit Care Med}, keywords = {exosome gene-expression bos}, language = {eng}, medline-pst = {ppublish}, month = Jul, number = 2, pages = {170--180}, pii = {rccm.201201-0117OC}, pmid = {22592804}, timestamp = {2012-07-20T00:11:21.000+0200}, title = {Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity.}, url = {http://dx.doi.org/10.1164/rccm.201201-0117OC}, username = {aorchid}, volume = 186, year = 2012 }