title: Pulmonary administration of phosphoinositide 3-kinase inhibitor is a curative treatment for chronic obstructive pulmonary disease by alveolar regeneration.
abstract: Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease, causing widespread and irreversible alveoli collapse. The discovery of a low-molecular-weight compound that induces regeneration of pulmonary alveoli is of utmost urgency to cure intractable pulmonary diseases such as COPD. However, a practically useful compound for regenerating pulmonary alveoli is yet to be reported. Previously, we have elucidated that Akt phosphorylation is involved in a differentiation-inducing molecular mechanism of human alveolar epithelial stem cells, which play a role in regenerating pulmonary alveoli. In the present study, we directed our attention to phosphoinositide 3-kinase (PI3K)-Akt signaling and examined whether PI3K inhibitors display the pulmonary alveolus regeneration. Three PI3K inhibitors with different PI3K subtype specificities (Wortmannin, AS605240, PIK-75 hydrochloride) were tested for the differentiation-inducing effect on human alveolar epithelial stem cells, and Wortmannin demonstrated the most potent differentiation-inducing activity. We evaluated Akt phosphorylation in pulmonary tissues of an elastase-induced murine COPD model and found that Akt phosphorylation in the pulmonary tissue was enhanced in the murine COPD model compared with normal mice. Then, the alveolus-repairing effect of pulmonary administration of Wortmannin to murine COPD model was evaluated using X-ray CT analysis and hematoxylin-eosin staining. As a result, alveolar damages were repaired in the Wortmannin-administered group to a similar level of normal mice. Furthermore, pulmonary administration of Wortmannin induced a significant recovery of the respiratory function, compared to the control group. These results indicate that Wortmannin is capable of inducing differentiation of human alveolar epithelial stem cells and represents a promising drug candidate for curative treatment of pulmonary alveolar destruction in COPD.
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address: horiguchim@rs.tus.ac.jp.
authors.forename: Michiko
authors.initials: M
authors.lastname: Horiguchi
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Oiso
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Motomura
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address: chikamasa_yamashita@rs.tus.ac.jp.
authors.forename: Chikamasa
authors.initials: C
authors.lastname: Yamashita
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000627:therapeutic use*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000473:pathology; D011810:Quinoxalines / Q000008:administration & dosage / Q000627:therapeutic use*; D012038:Regeneration / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*; D000077191:Wortmannin
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D000730:Androstadienes; D006835:Hydrazones; C549211:PIK 75; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; D045162:Thiazolidinediones; D000077191:Wortmannin
keywords: Akt; Alveolar regeneration; Chronic obstructive pulmonary disease (COPD); Phosphoinositide 3-kinase (PI3K); Wortmannin