Tetraspanin CD151 protects against pulmonary fibrosis by maintaining epithelial integrity.

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.

• Authors: Kazuyuki Tsujino, Yoshito Takeda, Toru Arai, Yasushi Shintani, Ryosaku Inagaki, Hiroyuki Saiga, Takeo Iwasaki, Satoshi Tetsumoto, Yingji Jin, Shoichi Ihara, Toshiyuki Minami, Mayumi Suzuki, Izumi Nagatomo, Koji Inoue, Hiroshi Kida, Takashi Kijima, Mari Ito, Masanori Kitaichi, Yoshikazu Inoue, Isao Tachibana, Kiyoshi Takeda, Meinoshin Okumura, Martin E Hemler, Atsushi Kumanogoh
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 186 Issue 2 Pg. 170-80 (Jul 15 2012) ISSN: 1535-4970 [Electronic] United States
• PMID: 22592804 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cd151 protein, mouse
• Smad2 Protein
• Tetraspanin 24
• Bleomycin

Topics

• Animals
• Bleomycin (pharmacology)
• Disease Models, Animal
• Fibroblasts (physiology)
• Humans
• Lung (physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• Phosphorylation
• Pulmonary Fibrosis (chemically induced, genetics, physiopathology)
• Smad2 Protein (metabolism)
• Tetraspanin 24 (physiology)