Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice

Abstract Influenza remains a major cause of death and disability with limited treatment options. Studies of acute lung injury have identified angiopoietin‐2 (Ang‐2) as a key prognostic marker and a potential mediator of Acute respiratory distress syndrome. However, the role of Ang‐2 in viral pneumon...

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Autores principales:	Jeffrey E. Gotts, Mazharul Maishan, Lauren Chun, Xiaohui Fang, Chun‐Ya Han, Venice Chiueh, Aarif Y. Khakoo, TaeWeon Lee, Marina Stolina, Michael A. Matthay
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	angiopoietin‐2 influenza pneumonia pulmonary edema viral lung injury Physiology QP1-981
Acceso en línea:	https://doaj.org/article/b29d331877234c9bb8ba6528693709e0
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spelling	oai:doaj.org-article:b29d331877234c9bb8ba6528693709e02021-11-15T09:54:40ZDelayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice2051-817X10.14814/phy2.15081https://doaj.org/article/b29d331877234c9bb8ba6528693709e02021-11-01T00:00:00Zhttps://doi.org/10.14814/phy2.15081https://doaj.org/toc/2051-817XAbstract Influenza remains a major cause of death and disability with limited treatment options. Studies of acute lung injury have identified angiopoietin‐2 (Ang‐2) as a key prognostic marker and a potential mediator of Acute respiratory distress syndrome. However, the role of Ang‐2 in viral pneumonia remains poorly defined. This study characterized the time course of lung Ang‐2 expression in severe influenza pneumonia and tested the therapeutic potential of Ang‐2 inhibition. We inoculated adult mice with influenza A (PR8 strain) and measured angiopoietin‐1 (Ang‐1), Ang‐2, and Tie2 expressions during the evolution of inflammatory lung injury over the first 7 days post‐infection (dpi). We tested a peptide‐antibody inhibitor of Ang‐2, L1‐7, administered at 2, 4, and 6 dpi and measured arterial oxygen saturation, survival, pulmonary edema, inflammatory cytokines, and viral load. Finally, we infected primary human alveolar type II epithelial (AT2) cells grown in air‐liquid interface culture with influenza and measured Ang‐2 RNA expression. Influenza caused severe lung injury between 5 and 7 dpi in association with increased Ang‐2 lung RNA and a dramatic increase in Ang‐2 protein in bronchoalveolar lavage. Inhibition of Ang‐2 improved oxygenation and survival and reduced pulmonary edema and alveolar‐capillary barrier permeability to protein without major effects on inflammation or viral load. Finally, influenza increased the expression of Ang‐2 RNA in human AT2 cells. The increased Ang‐2 levels in the airspaces during severe influenza pneumonia and the improvement in clinically relevant outcomes after Ang‐2 antagonism suggest that the Ang‐1/Ang‐2 Tie‐2 signaling axis is a promising therapeutic target in influenza and potentially other causes of viral pneumonia.Jeffrey E. GottsMazharul MaishanLauren ChunXiaohui FangChun‐Ya HanVenice ChiuehAarif Y. KhakooTaeWeon LeeMarina StolinaMichael A. MatthayWileyarticleangiopoietin‐2influenzapneumoniapulmonary edemaviral lung injuryPhysiologyQP1-981ENPhysiological Reports, Vol 9, Iss 21, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	angiopoietin‐2 influenza pneumonia pulmonary edema viral lung injury Physiology QP1-981
spellingShingle	angiopoietin‐2 influenza pneumonia pulmonary edema viral lung injury Physiology QP1-981 Jeffrey E. Gotts Mazharul Maishan Lauren Chun Xiaohui Fang Chun‐Ya Han Venice Chiueh Aarif Y. Khakoo TaeWeon Lee Marina Stolina Michael A. Matthay Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice
description	Abstract Influenza remains a major cause of death and disability with limited treatment options. Studies of acute lung injury have identified angiopoietin‐2 (Ang‐2) as a key prognostic marker and a potential mediator of Acute respiratory distress syndrome. However, the role of Ang‐2 in viral pneumonia remains poorly defined. This study characterized the time course of lung Ang‐2 expression in severe influenza pneumonia and tested the therapeutic potential of Ang‐2 inhibition. We inoculated adult mice with influenza A (PR8 strain) and measured angiopoietin‐1 (Ang‐1), Ang‐2, and Tie2 expressions during the evolution of inflammatory lung injury over the first 7 days post‐infection (dpi). We tested a peptide‐antibody inhibitor of Ang‐2, L1‐7, administered at 2, 4, and 6 dpi and measured arterial oxygen saturation, survival, pulmonary edema, inflammatory cytokines, and viral load. Finally, we infected primary human alveolar type II epithelial (AT2) cells grown in air‐liquid interface culture with influenza and measured Ang‐2 RNA expression. Influenza caused severe lung injury between 5 and 7 dpi in association with increased Ang‐2 lung RNA and a dramatic increase in Ang‐2 protein in bronchoalveolar lavage. Inhibition of Ang‐2 improved oxygenation and survival and reduced pulmonary edema and alveolar‐capillary barrier permeability to protein without major effects on inflammation or viral load. Finally, influenza increased the expression of Ang‐2 RNA in human AT2 cells. The increased Ang‐2 levels in the airspaces during severe influenza pneumonia and the improvement in clinically relevant outcomes after Ang‐2 antagonism suggest that the Ang‐1/Ang‐2 Tie‐2 signaling axis is a promising therapeutic target in influenza and potentially other causes of viral pneumonia.
format	article
author	Jeffrey E. Gotts Mazharul Maishan Lauren Chun Xiaohui Fang Chun‐Ya Han Venice Chiueh Aarif Y. Khakoo TaeWeon Lee Marina Stolina Michael A. Matthay
author_facet	Jeffrey E. Gotts Mazharul Maishan Lauren Chun Xiaohui Fang Chun‐Ya Han Venice Chiueh Aarif Y. Khakoo TaeWeon Lee Marina Stolina Michael A. Matthay
author_sort	Jeffrey E. Gotts
title	Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice
title_short	Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice
title_full	Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice
title_fullStr	Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice
title_full_unstemmed	Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice
title_sort	delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/b29d331877234c9bb8ba6528693709e0
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Delayed angiopoietin‐2 blockade reduces influenza‐induced lung injury and improves survival in mice

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