title: Pulmonary administration of integrin-nanoparticles regenerates collapsed alveoli.
abstract: Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease, causes widespread and irreversible alveoli collapse. In search of a treatment target molecule, which is able to regenerate collapsed alveoli, we sought to identify a factor that induces differentiation in human alveolar epithelial stem cells using all-trans retinoic acid (ATRA), whose alveolar repair capacity has been reported in animal experiments. When human alveolar epithelial stem cells were exposed to ATRA at a concentration of 10μM for over seven days, approximately 20% of the cells differentiated into each of the type-I and type-II alveolar epithelial cells that constitute the alveoli. In a microarray analysis, integrin-α1 and integrin-β3 showed the largest variation in the ATRA-treated group compared with the controls. Furthermore, the effect of the induction of differentiation in human alveolar epithelial stem cells using ATRA was suppressed by approximately one-fourth by siRNA treatments with integrin α1 and integrin β3. These results suggested that integrin α1 and β3 are factors responsible for the induction of differentiation in human alveolar epithelial stem cells. We accordingly investigated whether integrin nanoparticles also had a regenerative effect in vivo. Elastase-induced COPD model mouse was produced, and the alveolar repair effect of pulmonary administration using nanoparticles of integrin protein was evaluated by X-ray CT scanning. Improvement in the CT value in comparison with an untreated group indicated that there was an alveolar repair effect. In this study, it was shown that the differentiation-inducing effect on human alveolar epithelial stem cells by ATRA was induced by increased expression of integrin, and that the induced integrin enhanced phosphorylation signaling of AKT, resulting in inducing differentiations. Furthermore, the study demonstrated that lung administration of nanoparticles with increased solubility and stability of integrin repaired the alveolus of an Elastase-induced COPD model mouse. Those results show that those integrin nanoparticles are effective as novel COPD treatment target compounds.
authors: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Science, 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: Michiko
authors: M
authors: Horiguchi
authors: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Hisako
authors: H
authors: Kojima
authors: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Hitomi
authors: H
authors: Sakai
authors: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, 2-1 Aobaku, Sendai 980-8575 Japan.
authors: Hiroshi
authors: H
authors: Kubo
authors: Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Science, 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: Chikamasa
authors: C
authors: Yamashita
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005960:Glucosides / Q000737:chemistry; D006801:Humans; D039222:Integrin alpha1beta1 / Q000008:administration & dosage* / Q000235:genetics; D039302:Integrin alphaVbeta3 / Q000008:administration & dosage* / Q000235:genetics; D008297:Male; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010196:Pancreatic Elastase; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D012038:Regeneration / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D014212:Tretinoin / Q000008:administration & dosage*
chemical_list: D005960:Glucosides; D039222:Integrin alpha1beta1; D039302:Integrin alphaVbeta3; D014212:Tretinoin; C040358:dodecyl maltoside; D010196:Pancreatic Elastase
keywords: Alveolar regeneration; Chronic obstructive pulmonary disease (COPD); Extracellular matrix (ECM); Integrin; Nanoparticles; Pulmonary administration