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Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity

In acute lung injury, the lung endothelial barrier is compromised. Loss of endothelial barrier integrity occurs in association with decreased levels of the tight junction protein claudin-5. Restoration of their levels by gene transfection may improve the vascular barrier, but how to limit transfecti...

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Autores principales: Sanwal, Rajiv, Mintsopoulos, Victoria, Ditmans, Mihails, Lang, Alice, Latreille, Elyse, Ghaffari, Siavash, Khosraviani, Negar, Karshafian, Raffi, Leong-Poi, Howard, Hwang, David M., Brochard, Laurent, Goffi, Alberto, Slutsky, Arthur S., Lee, Warren L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Physiological Society 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393345/
https://www.ncbi.nlm.nih.gov/pubmed/37310768
http://dx.doi.org/10.1152/ajplung.00107.2023
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author Sanwal, Rajiv
Mintsopoulos, Victoria
Ditmans, Mihails
Lang, Alice
Latreille, Elyse
Ghaffari, Siavash
Khosraviani, Negar
Karshafian, Raffi
Leong-Poi, Howard
Hwang, David M.
Brochard, Laurent
Goffi, Alberto
Slutsky, Arthur S.
Lee, Warren L.
author_facet Sanwal, Rajiv
Mintsopoulos, Victoria
Ditmans, Mihails
Lang, Alice
Latreille, Elyse
Ghaffari, Siavash
Khosraviani, Negar
Karshafian, Raffi
Leong-Poi, Howard
Hwang, David M.
Brochard, Laurent
Goffi, Alberto
Slutsky, Arthur S.
Lee, Warren L.
author_sort Sanwal, Rajiv
collection PubMed
description In acute lung injury, the lung endothelial barrier is compromised. Loss of endothelial barrier integrity occurs in association with decreased levels of the tight junction protein claudin-5. Restoration of their levels by gene transfection may improve the vascular barrier, but how to limit transfection solely to regions of the lung that are injured is unknown. We hypothesized that thoracic ultrasound in combination with intravenous microbubbles (USMBs) could be used to achieve regional gene transfection in injured lung regions and improve endothelial barrier function. Since air blocks ultrasound energy, insonation of the lung is only achieved in areas of lung injury (edema and atelectasis); healthy lung is spared. Cavitation of the microbubbles achieves local tissue transfection. Here we demonstrate successful USMB-mediated gene transfection in the injured lungs of mice. After thoracic insonation, transfection was confined to the lung and only occurred in the setting of injured (but not healthy) lung. In a mouse model of acute lung injury, we observed downregulation of endogenous claudin-5 and an acute improvement in lung vascular leakage and in oxygenation after claudin-5 overexpression by transfection. The improvement occurred without any impairment of the immune response as measured by pathogen clearance, alveolar cytokines, and lung histology. In conclusion, USMB-mediated transfection targets injured lung regions and is a novel approach to the treatment of lung injury. NEW & NOTEWORTHY Acute respiratory distress syndrome is characterized by spatial heterogeneity, with severely injured lung regions adjacent to relatively normal areas. This makes targeting treatment to the injured regions difficult. Here we use thoracic ultrasound and intravenous microbubbles (USMBs) to direct gene transfection specifically to injured lung regions. Transfection of the tight junction protein claudin-5 improved oxygenation and decreased vascular leakage without impairing innate immunity. These findings suggest that USMB is a novel treatment for ARDS.
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spelling pubmed-103933452023-08-02 Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity Sanwal, Rajiv Mintsopoulos, Victoria Ditmans, Mihails Lang, Alice Latreille, Elyse Ghaffari, Siavash Khosraviani, Negar Karshafian, Raffi Leong-Poi, Howard Hwang, David M. Brochard, Laurent Goffi, Alberto Slutsky, Arthur S. Lee, Warren L. Am J Physiol Lung Cell Mol Physiol Short Report In acute lung injury, the lung endothelial barrier is compromised. Loss of endothelial barrier integrity occurs in association with decreased levels of the tight junction protein claudin-5. Restoration of their levels by gene transfection may improve the vascular barrier, but how to limit transfection solely to regions of the lung that are injured is unknown. We hypothesized that thoracic ultrasound in combination with intravenous microbubbles (USMBs) could be used to achieve regional gene transfection in injured lung regions and improve endothelial barrier function. Since air blocks ultrasound energy, insonation of the lung is only achieved in areas of lung injury (edema and atelectasis); healthy lung is spared. Cavitation of the microbubbles achieves local tissue transfection. Here we demonstrate successful USMB-mediated gene transfection in the injured lungs of mice. After thoracic insonation, transfection was confined to the lung and only occurred in the setting of injured (but not healthy) lung. In a mouse model of acute lung injury, we observed downregulation of endogenous claudin-5 and an acute improvement in lung vascular leakage and in oxygenation after claudin-5 overexpression by transfection. The improvement occurred without any impairment of the immune response as measured by pathogen clearance, alveolar cytokines, and lung histology. In conclusion, USMB-mediated transfection targets injured lung regions and is a novel approach to the treatment of lung injury. NEW & NOTEWORTHY Acute respiratory distress syndrome is characterized by spatial heterogeneity, with severely injured lung regions adjacent to relatively normal areas. This makes targeting treatment to the injured regions difficult. Here we use thoracic ultrasound and intravenous microbubbles (USMBs) to direct gene transfection specifically to injured lung regions. Transfection of the tight junction protein claudin-5 improved oxygenation and decreased vascular leakage without impairing innate immunity. These findings suggest that USMB is a novel treatment for ARDS. American Physiological Society 2023-08-01 2023-06-13 /pmc/articles/PMC10393345/ /pubmed/37310768 http://dx.doi.org/10.1152/ajplung.00107.2023 Text en Copyright © 2023 The Authors. https://creativecommons.org/licenses/by/4.0/Licensed under Creative Commons Attribution CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/) . Published by the American Physiological Society.
spellingShingle Short Report
Sanwal, Rajiv
Mintsopoulos, Victoria
Ditmans, Mihails
Lang, Alice
Latreille, Elyse
Ghaffari, Siavash
Khosraviani, Negar
Karshafian, Raffi
Leong-Poi, Howard
Hwang, David M.
Brochard, Laurent
Goffi, Alberto
Slutsky, Arthur S.
Lee, Warren L.
Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity
title Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity
title_full Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity
title_fullStr Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity
title_full_unstemmed Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity
title_short Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity
title_sort ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity
topic Short Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393345/
https://www.ncbi.nlm.nih.gov/pubmed/37310768
http://dx.doi.org/10.1152/ajplung.00107.2023
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