Epithelial Pten controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity. 2013

Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

BACKGROUND Injury to alveolar epithelial cells (AECs) and to their repair process is integral to the pathogenesis of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF). The mechanisms regulating the integrity of AECs and their intrinsic regulators remain unclear. Pten is a tumor suppressor, and its function in epithelial cells during organ fibrosis is unknown. OBJECTIVE To determine the role of epithelial Pten in ALI and lung fibrosis. METHODS Bronchioalveolar epithelium-specific Pten-deleted SP-C-rtTA/(tetO)(7)-Cre/Pten(Δ/Δ) (SOPten(Δ/Δ)) mice were studied by structural, biochemical, and physiologic analyses and compared with wild-type mice. Further mechanistic studies were performed in vivo, in vitro, and on samples from patients with IPF. RESULTS SOPten(Δ/Δ) mice demonstrated exacerbated alveolar flooding and subsequent augmented lung scarring with enhanced disassembly of tight junctions (TJs) of AECs and degradation of basement membranes. The induction of dominant negative PTEN gene in lung epithelial cells led to augmented transforming growth factor-1-induced disruptions of TJs. Epithelial-derived myofibroblasts were increased in the epithelium-specific Pten-deficient mice. The lungs of bleomycin-treated SOPten(Δ/Δ) mice showed increased pAkt, pS6K, Snail, and matrix metalloproteinase expressions and decreased claudin-4, E-cadherin, and laminin-β1 expressions. Akt inactivation definitively saved SOPten(Δ/Δ) mice through amelioration of ALI and retention of AEC integrity. We detected a reduction of PTEN expression and AKT hyperactivation in the AECs of human IPF lungs. CONCLUSIONS Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.

UI MeSH Term Description Entries
D011650 Pulmonary Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Alveoli, Pulmonary,Alveolus, Pulmonary,Pulmonary Alveolus
D011658 Pulmonary Fibrosis A process in which normal lung tissues are progressively replaced by FIBROBLASTS and COLLAGEN causing an irreversible loss of the ability to transfer oxygen into the bloodstream via PULMONARY ALVEOLI. Patients show progressive DYSPNEA finally resulting in death. Alveolitis, Fibrosing,Idiopathic Diffuse Interstitial Pulmonary Fibrosis,Fibroses, Pulmonary,Fibrosis, Pulmonary,Pulmonary Fibroses,Alveolitides, Fibrosing,Fibrosing Alveolitides,Fibrosing Alveolitis
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004847 Epithelial Cells Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells. Adenomatous Epithelial Cells,Columnar Glandular Epithelial Cells,Cuboidal Glandular Epithelial Cells,Glandular Epithelial Cells,Squamous Cells,Squamous Epithelial Cells,Transitional Epithelial Cells,Adenomatous Epithelial Cell,Cell, Adenomatous Epithelial,Cell, Epithelial,Cell, Glandular Epithelial,Cell, Squamous,Cell, Squamous Epithelial,Cell, Transitional Epithelial,Cells, Adenomatous Epithelial,Cells, Epithelial,Cells, Glandular Epithelial,Cells, Squamous,Cells, Squamous Epithelial,Cells, Transitional Epithelial,Epithelial Cell,Epithelial Cell, Adenomatous,Epithelial Cell, Glandular,Epithelial Cell, Squamous,Epithelial Cell, Transitional,Epithelial Cells, Adenomatous,Epithelial Cells, Glandular,Epithelial Cells, Squamous,Epithelial Cells, Transitional,Glandular Epithelial Cell,Squamous Cell,Squamous Epithelial Cell,Transitional Epithelial Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D051059 PTEN Phosphohydrolase A lipid phosphatase that contains a C2 DOMAIN and acts on phosphatidylinositol-3,4,5-trisphosphate to regulate various SIGNAL TRANSDUCTION PATHWAYS. It modulates CELL GROWTH PROCESSES; CELL MIGRATION; and APOPTOSIS. Mutations in PTEN are associated with COWDEN DISEASE and PROTEUS SYNDROME as well as NEOPLASTIC CELL TRANSFORMATION. MMAC1 Protein,Mutated In Multiple Advanced Cancers 1 Protein,PTEN Phosphatase,PTEN Protein,PTEN Protein Phosphatase,Phosphatase and Tensin Homologue on Chromosome Ten Protein,Phosphatase, PTEN,Phosphatase, PTEN Protein,Phosphohydrolase, PTEN,Protein Phosphatase, PTEN
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055371 Acute Lung Injury A condition of lung damage that is characterized by bilateral pulmonary infiltrates (PULMONARY EDEMA) rich in NEUTROPHILS, and in the absence of clinical HEART FAILURE. This can represent a spectrum of pulmonary lesions, endothelial and epithelial, due to numerous factors (physical, chemical, or biological). Lung Injury, Acute,Acute Lung Injuries,Lung Injuries, Acute
D018345 Mice, Knockout Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes. Knockout Mice,Mice, Knock-out,Mouse, Knockout,Knock-out Mice,Knockout Mouse,Mice, Knock out

Related Publications

Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
January 2021, International journal of medical sciences,
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
December 2023, Naunyn-Schmiedeberg's archives of pharmacology,
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
November 1993, New horizons (Baltimore, Md.),
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
January 2008, Masui. The Japanese journal of anesthesiology,
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
February 2011, Journal of anesthesia,
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
May 2024, International immunopharmacology,
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
August 2022, American journal of respiratory and critical care medicine,
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
June 2022, Aging and disease,
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
February 2019, Aging cell,
Kahori Miyoshi, and Shigehisa Yanagi, and Kohichi Kawahara, and Miki Nishio, and Hironobu Tsubouchi, and Yoshifumi Imazu, and Ryusuke Koshida, and Nobuhiro Matsumoto, and Akiko Taguchi, and Shu-ichi Yamashita, and Akira Suzuki, and Masamitsu Nakazato
January 2020, Cell death discovery,
Copied contents to your clipboard!