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Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel

There are no targeted medical therapies for Acute Lung Injury (ALI) or its most severe form acute respiratory distress syndrome (ARDS). Infections are the most common cause of ALI/ARDS and these disorders present clinically with alveolar inflammation and barrier dysfunction due to the influx of neut...

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Detalles Bibliográficos
Autores principales: Zhao, Ruiming, Lopez, Benjamin, Schwingshackl, Andreas, Goldstein, Steve A.N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843441/
https://www.ncbi.nlm.nih.gov/pubmed/36660473
http://dx.doi.org/10.1016/j.isci.2022.105901
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author Zhao, Ruiming
Lopez, Benjamin
Schwingshackl, Andreas
Goldstein, Steve A.N.
author_facet Zhao, Ruiming
Lopez, Benjamin
Schwingshackl, Andreas
Goldstein, Steve A.N.
author_sort Zhao, Ruiming
collection PubMed
description There are no targeted medical therapies for Acute Lung Injury (ALI) or its most severe form acute respiratory distress syndrome (ARDS). Infections are the most common cause of ALI/ARDS and these disorders present clinically with alveolar inflammation and barrier dysfunction due to the influx of neutrophils and inflammatory mediator secretion. We designed the C6 peptide to inhibit voltage-gated proton channels (Hv1) and demonstrated that it suppressed the release of reactive oxygen species (ROS) and proteases from neutrophils in vitro. We now show that intravenous C6 counteracts bacterial lipopolysaccharide (LPS)-induced ALI in mice, and suppresses the accumulation of neutrophils, ROS, and proinflammatory cytokines in bronchoalveolar lavage fluid. Confirming the salutary effects of C6 are via Hv1, genetic deletion of the channel similarly protects mice from LPS-induced ALI. This report reveals that Hv1 is a key regulator of ALI, that Hv1 is a druggable target, and that C6 is a viable agent to treat ALI/ARDS.
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spelling pubmed-98434412023-01-18 Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel Zhao, Ruiming Lopez, Benjamin Schwingshackl, Andreas Goldstein, Steve A.N. iScience Article There are no targeted medical therapies for Acute Lung Injury (ALI) or its most severe form acute respiratory distress syndrome (ARDS). Infections are the most common cause of ALI/ARDS and these disorders present clinically with alveolar inflammation and barrier dysfunction due to the influx of neutrophils and inflammatory mediator secretion. We designed the C6 peptide to inhibit voltage-gated proton channels (Hv1) and demonstrated that it suppressed the release of reactive oxygen species (ROS) and proteases from neutrophils in vitro. We now show that intravenous C6 counteracts bacterial lipopolysaccharide (LPS)-induced ALI in mice, and suppresses the accumulation of neutrophils, ROS, and proinflammatory cytokines in bronchoalveolar lavage fluid. Confirming the salutary effects of C6 are via Hv1, genetic deletion of the channel similarly protects mice from LPS-induced ALI. This report reveals that Hv1 is a key regulator of ALI, that Hv1 is a druggable target, and that C6 is a viable agent to treat ALI/ARDS. Elsevier 2022-12-29 /pmc/articles/PMC9843441/ /pubmed/36660473 http://dx.doi.org/10.1016/j.isci.2022.105901 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Zhao, Ruiming
Lopez, Benjamin
Schwingshackl, Andreas
Goldstein, Steve A.N.
Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel
title Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel
title_full Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel
title_fullStr Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel
title_full_unstemmed Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel
title_short Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel
title_sort protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843441/
https://www.ncbi.nlm.nih.gov/pubmed/36660473
http://dx.doi.org/10.1016/j.isci.2022.105901
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