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Exogenous gene transfer of Rab(3)8 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats

BACKGROUND: Rab(3)8 small GTPase regulates intracellular transport in melanocytes and alveolar type II epithelial cells. Ruby rats carrying Rab(3)8 and other gene mutations exhibit oculocutaneous albinism, bleeding diathesis, and hence, are a rat model of human Hermansky-Pudlak syndrome (HPS). We pr...

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Autores principales: Osanai, Kazuhiro, Nakase, Keisuke, Sakuma, Takashi, Nishiki, Kazuaki, Nojiri, Masafumi, Kato, Ryo, Saito, Masatoshi, Fujimoto, Yuki, Mizuno, Shiro, Toga, Hirohisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402648/
https://www.ncbi.nlm.nih.gov/pubmed/28438206
http://dx.doi.org/10.1186/s12931-017-0549-2
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author Osanai, Kazuhiro
Nakase, Keisuke
Sakuma, Takashi
Nishiki, Kazuaki
Nojiri, Masafumi
Kato, Ryo
Saito, Masatoshi
Fujimoto, Yuki
Mizuno, Shiro
Toga, Hirohisa
author_facet Osanai, Kazuhiro
Nakase, Keisuke
Sakuma, Takashi
Nishiki, Kazuaki
Nojiri, Masafumi
Kato, Ryo
Saito, Masatoshi
Fujimoto, Yuki
Mizuno, Shiro
Toga, Hirohisa
author_sort Osanai, Kazuhiro
collection PubMed
description BACKGROUND: Rab(3)8 small GTPase regulates intracellular transport in melanocytes and alveolar type II epithelial cells. Ruby rats carrying Rab(3)8 and other gene mutations exhibit oculocutaneous albinism, bleeding diathesis, and hence, are a rat model of human Hermansky-Pudlak syndrome (HPS). We previously showed that Long Evans Cinnamon (LEC) rats, one strain of the Ruby rats, developed aberrant lung surfactant homeostasis with remarkably enlarged lamellar bodies in alveolar type II cells. METHODS: A replication-deficient recombinant adenovirus expressing rat Rab(3)8 (Ad-Rab(3)8) was constructed. Alveolar type II cells were isolated from the LEC rats and tested for lung surfactant phosphatidylcholine secretion. The rats were also examined whether exogenous expression of Ad- Rab(3)8 could rescue the altered lung surfactant homeostasis in the lungs. RESULTS: Isolated type II cells infected with Ad-Rab(3)8 exhibited improved secretion patterns of [(3)H]phosphatidylcholine, i.e. increased basal hyposecretion and decreased agonist-induced hypersecretion. Endobronchial administration of Ad-Rab(3)8 improved the morphology of type II cells and lamellar bodies, reducing their sizes close to those of wild-type rats. The increased amounts of phosphatidylcholine and surfactant protein B in the lamellar body fractions were decreased in the Ad-Rab(3)8 infected lungs. CONCLUSIONS: These results provide strong evidence that the aberrant lung surfactant homeostasis in the LEC rats is caused by Rab(3)8 deficit, and suggest that endobronchial delivery of the responsive transgene could be an effective method to ameliorate the abnormal lung phenotype in the animal model of HPS.
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spelling pubmed-54026482017-04-27 Exogenous gene transfer of Rab(3)8 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats Osanai, Kazuhiro Nakase, Keisuke Sakuma, Takashi Nishiki, Kazuaki Nojiri, Masafumi Kato, Ryo Saito, Masatoshi Fujimoto, Yuki Mizuno, Shiro Toga, Hirohisa Respir Res Research BACKGROUND: Rab(3)8 small GTPase regulates intracellular transport in melanocytes and alveolar type II epithelial cells. Ruby rats carrying Rab(3)8 and other gene mutations exhibit oculocutaneous albinism, bleeding diathesis, and hence, are a rat model of human Hermansky-Pudlak syndrome (HPS). We previously showed that Long Evans Cinnamon (LEC) rats, one strain of the Ruby rats, developed aberrant lung surfactant homeostasis with remarkably enlarged lamellar bodies in alveolar type II cells. METHODS: A replication-deficient recombinant adenovirus expressing rat Rab(3)8 (Ad-Rab(3)8) was constructed. Alveolar type II cells were isolated from the LEC rats and tested for lung surfactant phosphatidylcholine secretion. The rats were also examined whether exogenous expression of Ad- Rab(3)8 could rescue the altered lung surfactant homeostasis in the lungs. RESULTS: Isolated type II cells infected with Ad-Rab(3)8 exhibited improved secretion patterns of [(3)H]phosphatidylcholine, i.e. increased basal hyposecretion and decreased agonist-induced hypersecretion. Endobronchial administration of Ad-Rab(3)8 improved the morphology of type II cells and lamellar bodies, reducing their sizes close to those of wild-type rats. The increased amounts of phosphatidylcholine and surfactant protein B in the lamellar body fractions were decreased in the Ad-Rab(3)8 infected lungs. CONCLUSIONS: These results provide strong evidence that the aberrant lung surfactant homeostasis in the LEC rats is caused by Rab(3)8 deficit, and suggest that endobronchial delivery of the responsive transgene could be an effective method to ameliorate the abnormal lung phenotype in the animal model of HPS. BioMed Central 2017-04-24 2017 /pmc/articles/PMC5402648/ /pubmed/28438206 http://dx.doi.org/10.1186/s12931-017-0549-2 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Osanai, Kazuhiro
Nakase, Keisuke
Sakuma, Takashi
Nishiki, Kazuaki
Nojiri, Masafumi
Kato, Ryo
Saito, Masatoshi
Fujimoto, Yuki
Mizuno, Shiro
Toga, Hirohisa
Exogenous gene transfer of Rab(3)8 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats
title Exogenous gene transfer of Rab(3)8 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats
title_full Exogenous gene transfer of Rab(3)8 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats
title_fullStr Exogenous gene transfer of Rab(3)8 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats
title_full_unstemmed Exogenous gene transfer of Rab(3)8 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats
title_short Exogenous gene transfer of Rab(3)8 small GTPase ameliorates aberrant lung surfactant homeostasis in Ruby rats
title_sort exogenous gene transfer of rab(3)8 small gtpase ameliorates aberrant lung surfactant homeostasis in ruby rats
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402648/
https://www.ncbi.nlm.nih.gov/pubmed/28438206
http://dx.doi.org/10.1186/s12931-017-0549-2
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