Pulmonary administration of integrin-nanoparticles regenerates collapsed alveoli

Michiko Horiguchi, Hisako Kojima, Hitomi Sakai, Hiroshi Kubo, Chikamasa Yamashita

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 10 μM 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.

Original languageEnglish
Pages (from-to)167-174
Number of pages8
JournalJournal of Controlled Release
Volume187
DOIs
Publication statusPublished - 2014 Aug 10

Keywords

  • Alveolar regeneration
  • Chronic obstructive pulmonary disease (COPD)
  • Extracellular matrix (ECM)
  • Integrin
  • Nanoparticles
  • Pulmonary administration

ASJC Scopus subject areas

  • Pharmaceutical Science

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