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Actin fence therapy with exogenous V12Rac1 protects against acute lung injury
High mortality in acute lung injury (ALI) results from sustained proinflammatory signaling by alveolar receptors, such as TNF-α receptor type 1 (TNFR1). Factors that determine the sustained signaling are not known. Unexpectedly, optical imaging of live alveoli revealed a major TNF-α–induced surge of...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026177/ https://www.ncbi.nlm.nih.gov/pubmed/33749665 http://dx.doi.org/10.1172/jci.insight.135753 |
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author | Gusarova, Galina A. Das, Shonit R. Islam, Mohammad N. Westphalen, Kristin Jin, Guangchun Shmarakov, Igor O. Li, Li Bhattacharya, Sunita Bhattacharya, Jahar |
author_facet | Gusarova, Galina A. Das, Shonit R. Islam, Mohammad N. Westphalen, Kristin Jin, Guangchun Shmarakov, Igor O. Li, Li Bhattacharya, Sunita Bhattacharya, Jahar |
author_sort | Gusarova, Galina A. |
collection | PubMed |
description | High mortality in acute lung injury (ALI) results from sustained proinflammatory signaling by alveolar receptors, such as TNF-α receptor type 1 (TNFR1). Factors that determine the sustained signaling are not known. Unexpectedly, optical imaging of live alveoli revealed a major TNF-α–induced surge of alveolar TNFR1 due to a Ca(2+)-dependent mechanism that decreased the cortical actin fence. Mouse mortality due to inhaled LPS was associated with cofilin activation, actin loss, and the TNFR1 surge. The constitutively active form of the GTPase, Rac1 (V12Rac1), given intranasally (i.n.) as a noncovalent construct with a cell-permeable peptide, enhanced alveolar filamentous actin (F-actin) and blocked the TNFR1 surge. V12Rac1 also protected against ALI-induced mortality resulting from i.n. instillation of LPS or of Pseudomonas aeruginosa. We propose a potentially new therapeutic paradigm in which actin enhancement by exogenous Rac1 strengthens the alveolar actin fence, protecting against proinflammatory receptor hyperexpression, and therefore blocking ALI. |
format | Online Article Text |
id | pubmed-8026177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-80261772021-04-13 Actin fence therapy with exogenous V12Rac1 protects against acute lung injury Gusarova, Galina A. Das, Shonit R. Islam, Mohammad N. Westphalen, Kristin Jin, Guangchun Shmarakov, Igor O. Li, Li Bhattacharya, Sunita Bhattacharya, Jahar JCI Insight Research Article High mortality in acute lung injury (ALI) results from sustained proinflammatory signaling by alveolar receptors, such as TNF-α receptor type 1 (TNFR1). Factors that determine the sustained signaling are not known. Unexpectedly, optical imaging of live alveoli revealed a major TNF-α–induced surge of alveolar TNFR1 due to a Ca(2+)-dependent mechanism that decreased the cortical actin fence. Mouse mortality due to inhaled LPS was associated with cofilin activation, actin loss, and the TNFR1 surge. The constitutively active form of the GTPase, Rac1 (V12Rac1), given intranasally (i.n.) as a noncovalent construct with a cell-permeable peptide, enhanced alveolar filamentous actin (F-actin) and blocked the TNFR1 surge. V12Rac1 also protected against ALI-induced mortality resulting from i.n. instillation of LPS or of Pseudomonas aeruginosa. We propose a potentially new therapeutic paradigm in which actin enhancement by exogenous Rac1 strengthens the alveolar actin fence, protecting against proinflammatory receptor hyperexpression, and therefore blocking ALI. American Society for Clinical Investigation 2021-03-22 /pmc/articles/PMC8026177/ /pubmed/33749665 http://dx.doi.org/10.1172/jci.insight.135753 Text en © 2021 Gusarova et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Gusarova, Galina A. Das, Shonit R. Islam, Mohammad N. Westphalen, Kristin Jin, Guangchun Shmarakov, Igor O. Li, Li Bhattacharya, Sunita Bhattacharya, Jahar Actin fence therapy with exogenous V12Rac1 protects against acute lung injury |
title | Actin fence therapy with exogenous V12Rac1 protects against acute lung injury |
title_full | Actin fence therapy with exogenous V12Rac1 protects against acute lung injury |
title_fullStr | Actin fence therapy with exogenous V12Rac1 protects against acute lung injury |
title_full_unstemmed | Actin fence therapy with exogenous V12Rac1 protects against acute lung injury |
title_short | Actin fence therapy with exogenous V12Rac1 protects against acute lung injury |
title_sort | actin fence therapy with exogenous v12rac1 protects against acute lung injury |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026177/ https://www.ncbi.nlm.nih.gov/pubmed/33749665 http://dx.doi.org/10.1172/jci.insight.135753 |
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