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Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38

BACKGROUND: The ability of p38 to phosphorylate substrates in the nucleus and the role of nuclear p38 in the regulation of inflammation have focused attention on the subcellular localization of the kinase. Although it is clear that p38 shuttles to the nucleus upon stimulation, the mechanisms that re...

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Autores principales: Ding, Ning, Li, Huiqing, Zhang, Zengzhen, Jia, Haiyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198890/
https://www.ncbi.nlm.nih.gov/pubmed/37004548
http://dx.doi.org/10.1007/s00011-023-01727-x
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author Ding, Ning
Li, Huiqing
Zhang, Zengzhen
Jia, Haiyan
author_facet Ding, Ning
Li, Huiqing
Zhang, Zengzhen
Jia, Haiyan
author_sort Ding, Ning
collection PubMed
description BACKGROUND: The ability of p38 to phosphorylate substrates in the nucleus and the role of nuclear p38 in the regulation of inflammation have focused attention on the subcellular localization of the kinase. Although it is clear that p38 shuttles to the nucleus upon stimulation, the mechanisms that regulate p38 nuclear input in response to mechanical stretch remain to be determined. METHODS: Cyclic stretch (CS)-induced nuclear translocation of p38 was determined by Western blotting and immunofluorescence. The p38 interacting protein was identified using endogenous pull-down and protein binding assays. The potential role of importin-7 (Imp7) in CS-induced nuclear translocation of p38 and p38-dependent gene expression was confirmed using a series of in vitro and in vivo experiments. Furthermore, we tested the therapeutic potential of intratracheal administration of Imp7 siRNA-loaded nanoparticles in the ventilator-induced lung injury (VILI) mouse model. RESULTS: We show that CS induced phosphorylation-dependent nuclear translocation of p38, which required the involvement of microtubules and dynein. Endogenous pull-down assay revealed Imp7 to be a potential p38-interacting protein, and the direct interaction between p38 and Imp7 was confirmed by in vitro and in vivo binding assays. Furthermore, silencing Imp7 inhibited CS-induced nuclear translocation of p38 and subsequent cytokine production. Notably, intratracheal administration of Imp7 siRNA nanoparticles attenuated lung inflammation and histological damage in the VILI mouse model. CONCLUSIONS: Our findings uncover a key role for Imp7 in the process of p38 nuclear import after CS stimulation and highlight the potential of preventing p38 nuclear translocation in treatment of VILI.
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spelling pubmed-101988902023-05-21 Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38 Ding, Ning Li, Huiqing Zhang, Zengzhen Jia, Haiyan Inflamm Res Original Research Paper BACKGROUND: The ability of p38 to phosphorylate substrates in the nucleus and the role of nuclear p38 in the regulation of inflammation have focused attention on the subcellular localization of the kinase. Although it is clear that p38 shuttles to the nucleus upon stimulation, the mechanisms that regulate p38 nuclear input in response to mechanical stretch remain to be determined. METHODS: Cyclic stretch (CS)-induced nuclear translocation of p38 was determined by Western blotting and immunofluorescence. The p38 interacting protein was identified using endogenous pull-down and protein binding assays. The potential role of importin-7 (Imp7) in CS-induced nuclear translocation of p38 and p38-dependent gene expression was confirmed using a series of in vitro and in vivo experiments. Furthermore, we tested the therapeutic potential of intratracheal administration of Imp7 siRNA-loaded nanoparticles in the ventilator-induced lung injury (VILI) mouse model. RESULTS: We show that CS induced phosphorylation-dependent nuclear translocation of p38, which required the involvement of microtubules and dynein. Endogenous pull-down assay revealed Imp7 to be a potential p38-interacting protein, and the direct interaction between p38 and Imp7 was confirmed by in vitro and in vivo binding assays. Furthermore, silencing Imp7 inhibited CS-induced nuclear translocation of p38 and subsequent cytokine production. Notably, intratracheal administration of Imp7 siRNA nanoparticles attenuated lung inflammation and histological damage in the VILI mouse model. CONCLUSIONS: Our findings uncover a key role for Imp7 in the process of p38 nuclear import after CS stimulation and highlight the potential of preventing p38 nuclear translocation in treatment of VILI. Springer International Publishing 2023-04-01 2023 /pmc/articles/PMC10198890/ /pubmed/37004548 http://dx.doi.org/10.1007/s00011-023-01727-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Research Paper
Ding, Ning
Li, Huiqing
Zhang, Zengzhen
Jia, Haiyan
Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38
title Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38
title_full Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38
title_fullStr Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38
title_full_unstemmed Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38
title_short Inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38
title_sort inhibition of importin-7 attenuates ventilator-induced lung injury by targeting nuclear translocation of p38
topic Original Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198890/
https://www.ncbi.nlm.nih.gov/pubmed/37004548
http://dx.doi.org/10.1007/s00011-023-01727-x
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