title: Pulmonary administration of Am80 regenerates collapsed alveoli.
abstract: Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease, which causes widespread and irreversible alveoli collapse. Nevertheless, there is no effective drug therapy that regenerates lung tissue or prevents the progression of COPD and clinical management of patients remains mostly supportive. The aim of this study was to evaluate whether Am80 is useful as a novel pulmonary emphysema therapeutic drug. In this study, we treated the human alveolar epithelial stem cells with Am80 to clarify the differentiation-inducing mechanism and administrated Am80 transpulmonarily into elastase-induced COPD model mice to evaluate the effect of Am80 on pulmonary emphysema. First, we accordingly investigated whether Am80 had a differentiation-inducing effect on human alveolar epithelial stem cells, Am80 induced differentiation of human alveolar epithelial stem cells to alveolar type I and II cells dose dependently, and the proportion of differentiated into type I and type II alveolar epithelial cells as a result of treatment with 10 μM of Am80 for 7 days was approximately 20%. Second, we attempted to identify the major factor involved in the differentiation-inducing effect of human alveolar epithelial stem cells induced by Am80 using microarray analysis. In a microarray analysis, WNT1, lectin, SLIT, chordin, ck12, ck11, and neurexin3 showed the largest variation in the Am80-treated group compared with the controls. In quantitative polymerase-chain-reaction assay, Am80 resulted in significant reduction in the WNT1 expression ratio whereas increase in the neurexin3 expression ratio. We evaluated the repairs effect for collapsed alveoli by Am80 of pulmonary administration. In untreated and Am80-treated mice the average CT value at 2 days was, respectively, -506 and -439 and there was a significant difference. Likewise, the assessment of the distance between alveolar walls, Lm, confirmed that there was a significant difference between control (68.0±3.8 μm) and Am80-treated group (46.8±1.8 μm). These indicated that treatment with Am80 caused a reversal of lung tissue damage in elastase-induced COPD model mouse. Those results suggested that Am80 were effective as novel COPD therapeutic compounds.
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; Center for Physical Pharmaceutics, Research Institute for Science and Technology, 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: Chihiro
authors.initials: C
authors.lastname: Ozawa
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: Tomomi
authors.initials: T
authors.lastname: Akita
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Center for Physical Pharmaceutics, Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirota
authors.affiliation: Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya, Tokyo, 158-0094, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Center for Physical Pharmaceutics, Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terada
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Center for Physical Pharmaceutics, Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Makino
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, 2-1 Aobaku, Sendai, 980-8575, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubo
authors.affiliation: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Center for Physical Pharmaceutics, Research Institute for Science and Technology, 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: D000818:Animals; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D010196:Pancreatic Elastase; D011650:Pulmonary Alveoli / Q000187:drug effects*; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D001565:Benzoates; D018168:Receptors, Retinoic Acid; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D010196:Pancreatic Elastase
keywords: Alveolar regeneration; Am80 (Tamibarotene); Chronic obstructive pulmonary disease; Pulmonary administration