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Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury

Mechanical ventilation may cause ventilator-induced lung injury (VILI) in patients requiring ventilator support. Inhibition of autophagy is an important approach to ameliorate VILI as it always enhances lung injury after exposure to various stress agents. This study aimed to further reveal the poten...

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Autores principales: Wang, Zexu, Chen, Meizi, Pan, Xia, Wang, Li, Yin, Cheng, Lin, Qiuqi, Jiang, Jingjing, Zhang, Yunlei, Wan, Bing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Nature Singapore 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948466/
https://www.ncbi.nlm.nih.gov/pubmed/35334098
http://dx.doi.org/10.1007/s13577-022-00692-7
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author Wang, Zexu
Chen, Meizi
Pan, Xia
Wang, Li
Yin, Cheng
Lin, Qiuqi
Jiang, Jingjing
Zhang, Yunlei
Wan, Bing
author_facet Wang, Zexu
Chen, Meizi
Pan, Xia
Wang, Li
Yin, Cheng
Lin, Qiuqi
Jiang, Jingjing
Zhang, Yunlei
Wan, Bing
author_sort Wang, Zexu
collection PubMed
description Mechanical ventilation may cause ventilator-induced lung injury (VILI) in patients requiring ventilator support. Inhibition of autophagy is an important approach to ameliorate VILI as it always enhances lung injury after exposure to various stress agents. This study aimed to further reveal the potential mechanisms underlying the effects of geranylgeranyl diphosphate synthase large subunit 1 (GGPPS1) knockout and autophagy in VILI using C57BL/6 mice with lung-specific GGPPS1 knockout that were subjected to mechanical ventilation. The results demonstrate that GGPPS1 knockout mice exhibit significantly attenuated VILI based on the histologic score, the lung wet-to-dry ratio, total protein levels, neutrophils in bronchoalveolar lavage fluid, and reduced levels of inflammatory cytokines. Importantly, the expression levels of autophagy markers were obviously decreased in GGPPS1 knockout mice compared with wild-type mice. The inhibitory effects of GGPPS1 knockout on autophagy were further confirmed by measuring the ultrastructural change of lung tissues under transmission electron microscopy. In addition, knockdown of GGPPS1 in RAW264.7 cells reduced cyclic stretch-induced inflammation and autophagy. The benefits of GGPPS1 knockout for VILI can be partially eliminated through treatment with rapamycin. Further analysis revealed that Rab37 was significantly downregulated in GGPPS1 knockout mice after mechanical ventilation, while it was highly expressed in the control group. Simultaneously, Rab37 overexpression significantly enhances autophagy in cells that are treated with cyclin stretch, including GGPPS1 knockout cells. Collectively, our results indicate that GGPPS1 knockout results in reduced expression of Rab37 proteins, further restraining autophagy and VILI.
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spelling pubmed-89484662022-03-25 Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury Wang, Zexu Chen, Meizi Pan, Xia Wang, Li Yin, Cheng Lin, Qiuqi Jiang, Jingjing Zhang, Yunlei Wan, Bing Hum Cell Research Article Mechanical ventilation may cause ventilator-induced lung injury (VILI) in patients requiring ventilator support. Inhibition of autophagy is an important approach to ameliorate VILI as it always enhances lung injury after exposure to various stress agents. This study aimed to further reveal the potential mechanisms underlying the effects of geranylgeranyl diphosphate synthase large subunit 1 (GGPPS1) knockout and autophagy in VILI using C57BL/6 mice with lung-specific GGPPS1 knockout that were subjected to mechanical ventilation. The results demonstrate that GGPPS1 knockout mice exhibit significantly attenuated VILI based on the histologic score, the lung wet-to-dry ratio, total protein levels, neutrophils in bronchoalveolar lavage fluid, and reduced levels of inflammatory cytokines. Importantly, the expression levels of autophagy markers were obviously decreased in GGPPS1 knockout mice compared with wild-type mice. The inhibitory effects of GGPPS1 knockout on autophagy were further confirmed by measuring the ultrastructural change of lung tissues under transmission electron microscopy. In addition, knockdown of GGPPS1 in RAW264.7 cells reduced cyclic stretch-induced inflammation and autophagy. The benefits of GGPPS1 knockout for VILI can be partially eliminated through treatment with rapamycin. Further analysis revealed that Rab37 was significantly downregulated in GGPPS1 knockout mice after mechanical ventilation, while it was highly expressed in the control group. Simultaneously, Rab37 overexpression significantly enhances autophagy in cells that are treated with cyclin stretch, including GGPPS1 knockout cells. Collectively, our results indicate that GGPPS1 knockout results in reduced expression of Rab37 proteins, further restraining autophagy and VILI. Springer Nature Singapore 2022-03-25 2022 /pmc/articles/PMC8948466/ /pubmed/35334098 http://dx.doi.org/10.1007/s13577-022-00692-7 Text en © The Author(s) under exclusive licence to Japan Human Cell Society 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Research Article
Wang, Zexu
Chen, Meizi
Pan, Xia
Wang, Li
Yin, Cheng
Lin, Qiuqi
Jiang, Jingjing
Zhang, Yunlei
Wan, Bing
Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury
title Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury
title_full Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury
title_fullStr Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury
title_full_unstemmed Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury
title_short Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury
title_sort knockout of ggpps1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948466/
https://www.ncbi.nlm.nih.gov/pubmed/35334098
http://dx.doi.org/10.1007/s13577-022-00692-7
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