TY - JOUR
T1 - Pulmonary administration of Am80 regenerates collapsed alveoli
AU - Sakai, Hitomi
AU - Horiguchi, Michiko
AU - Ozawa, Chihiro
AU - Akita, Tomomi
AU - Hirota, Keiji
AU - Shudo, Koichi
AU - Terada, Hiroshi
AU - Makino, Kimiko
AU - Kubo, Hiroshi
AU - Yamashita, Chikamasa
N1 - Funding Information:
This investigation was supported in parts by The Mochida Memorial Foundation for Medical and Pharmaceutical Research [Michiko Horiguchi] and partially supported by The Hamaguchi Foundation for the Advancement of Biochemistry [Michiko Horiguchi] , the Grant-in-Aid for Research Activity Start-up [Michiko Horiguchi, 24890257 ], and the Grant-in-Aid for Young Scientists (B) [Michiko Horiguchi, 25860029 ] from the Japan Society for the Promotion of Science.
Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
PY - 2014/12/28
Y1 - 2014/12/28
N2 - 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.
AB - 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.
KW - Alveolar regeneration
KW - Am80 (Tamibarotene)
KW - Chronic obstructive pulmonary disease
KW - Pulmonary administration
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U2 - 10.1016/j.jconrel.2014.10.004
DO - 10.1016/j.jconrel.2014.10.004
M3 - Article
C2 - 25312542
AN - SCOPUS:84908167462
VL - 196
SP - 154
EP - 160
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -