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Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice

BACKGROUND: Increased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS syste...

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Autores principales: Noguchi, Shingo, Yatera, Kazuhiro, Wang, Ke-Yong, Oda, Keishi, Akata, Kentarou, Yamasaki, Kei, Kawanami, Toshinori, Ishimoto, Hiroshi, Toyohira, Yumiko, Shimokawa, Hiroaki, Yanagihara, Nobuyuki, Tsutsui, Masato, Mukae, Hiroshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237963/
https://www.ncbi.nlm.nih.gov/pubmed/25092105
http://dx.doi.org/10.1186/s12931-014-0092-3
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author Noguchi, Shingo
Yatera, Kazuhiro
Wang, Ke-Yong
Oda, Keishi
Akata, Kentarou
Yamasaki, Kei
Kawanami, Toshinori
Ishimoto, Hiroshi
Toyohira, Yumiko
Shimokawa, Hiroaki
Yanagihara, Nobuyuki
Tsutsui, Masato
Mukae, Hiroshi
author_facet Noguchi, Shingo
Yatera, Kazuhiro
Wang, Ke-Yong
Oda, Keishi
Akata, Kentarou
Yamasaki, Kei
Kawanami, Toshinori
Ishimoto, Hiroshi
Toyohira, Yumiko
Shimokawa, Hiroaki
Yanagihara, Nobuyuki
Tsutsui, Masato
Mukae, Hiroshi
author_sort Noguchi, Shingo
collection PubMed
description BACKGROUND: Increased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS system in the pathogenesis of pulmonary fibrosis still remain to be fully elucidated. The aim of the present study is to clarify the roles of NO and the NOS system in pulmonary fibrosis by using the mice lacking all three NOS isoforms. METHODS: Wild-type, single NOS knockout and triple NOS knockout (n/i/eNOS(−/−)) mice were administered bleomycin (BLM) intraperitoneally at a dose of 8.0 mg/kg/day for 10 consecutive days. Two weeks after the end of the procedure, the fibrotic and inflammatory changes of the lung were evaluated. In addition, we evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS(−/−) mice with BLM-induced pulmonary fibrosis. RESULTS: The histopathological findings, collagen content and the total cell number in bronchoalveolar lavage fluid were the most severe/highest in the n/i/eNOS(−/−) mice. Long-term treatment with the supplemental NO donor in n/i/eNOS(−/−) mice significantly prevented the progression of the histopathological findings and the increase of the collagen content in the lungs. CONCLUSIONS: These results provide the first direct evidence that a lack of all three NOS isoforms led to a deterioration of pulmonary fibrosis in a BLM-treated murine model. We speculate that the entire endogenous NO and NOS system plays an important protective role in the pathogenesis of pulmonary fibrosis.
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spelling pubmed-42379632014-11-21 Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice Noguchi, Shingo Yatera, Kazuhiro Wang, Ke-Yong Oda, Keishi Akata, Kentarou Yamasaki, Kei Kawanami, Toshinori Ishimoto, Hiroshi Toyohira, Yumiko Shimokawa, Hiroaki Yanagihara, Nobuyuki Tsutsui, Masato Mukae, Hiroshi Respir Res Research BACKGROUND: Increased expression of nitric oxide synthase (NOS) and an increase in plasma nitrite plus nitrate (NOx) have been reported in patients with pulmonary fibrosis, suggesting that nitric oxide (NO) plays an important role in its development. However, the roles of the entire NO and NOS system in the pathogenesis of pulmonary fibrosis still remain to be fully elucidated. The aim of the present study is to clarify the roles of NO and the NOS system in pulmonary fibrosis by using the mice lacking all three NOS isoforms. METHODS: Wild-type, single NOS knockout and triple NOS knockout (n/i/eNOS(−/−)) mice were administered bleomycin (BLM) intraperitoneally at a dose of 8.0 mg/kg/day for 10 consecutive days. Two weeks after the end of the procedure, the fibrotic and inflammatory changes of the lung were evaluated. In addition, we evaluated the effects of long-term treatment with isosorbide dinitrate, a NO donor, on the n/i/eNOS(−/−) mice with BLM-induced pulmonary fibrosis. RESULTS: The histopathological findings, collagen content and the total cell number in bronchoalveolar lavage fluid were the most severe/highest in the n/i/eNOS(−/−) mice. Long-term treatment with the supplemental NO donor in n/i/eNOS(−/−) mice significantly prevented the progression of the histopathological findings and the increase of the collagen content in the lungs. CONCLUSIONS: These results provide the first direct evidence that a lack of all three NOS isoforms led to a deterioration of pulmonary fibrosis in a BLM-treated murine model. We speculate that the entire endogenous NO and NOS system plays an important protective role in the pathogenesis of pulmonary fibrosis. BioMed Central 2014 2014-08-05 /pmc/articles/PMC4237963/ /pubmed/25092105 http://dx.doi.org/10.1186/s12931-014-0092-3 Text en Copyright © 2014 Noguchi et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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
Noguchi, Shingo
Yatera, Kazuhiro
Wang, Ke-Yong
Oda, Keishi
Akata, Kentarou
Yamasaki, Kei
Kawanami, Toshinori
Ishimoto, Hiroshi
Toyohira, Yumiko
Shimokawa, Hiroaki
Yanagihara, Nobuyuki
Tsutsui, Masato
Mukae, Hiroshi
Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice
title Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice
title_full Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice
title_fullStr Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice
title_full_unstemmed Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice
title_short Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice
title_sort nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237963/
https://www.ncbi.nlm.nih.gov/pubmed/25092105
http://dx.doi.org/10.1186/s12931-014-0092-3
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