HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.

<h4>Background</h4>While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant st...

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Autores principales:	Tobias Eckle, Kelley Brodsky, Megan Bonney, Thomas Packard, Jun Han, Christoph H Borchers, Thomas J Mariani, Douglas J Kominsky, Michel Mittelbronn, Holger K Eltzschig
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/59694fe8c1974a1ea3a346285a25ce33
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spelling	oai:doaj.org-article:59694fe8c1974a1ea3a346285a25ce332021-11-18T05:37:49ZHIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.1544-91731545-788510.1371/journal.pbio.1001665https://doaj.org/article/59694fe8c1974a1ea3a346285a25ce332013-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24086109/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885<h4>Background</h4>While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection.<h4>Methods and findings</h4>To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions--an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of ¹³C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A.<h4>Conclusions</h4>These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation.Tobias EckleKelley BrodskyMegan BonneyThomas PackardJun HanChristoph H BorchersThomas J MarianiDouglas J KominskyMichel MittelbronnHolger K EltzschigPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 11, Iss 9, p e1001665 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Tobias Eckle Kelley Brodsky Megan Bonney Thomas Packard Jun Han Christoph H Borchers Thomas J Mariani Douglas J Kominsky Michel Mittelbronn Holger K Eltzschig HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
description	<h4>Background</h4>While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection.<h4>Methods and findings</h4>To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions--an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of ¹³C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A.<h4>Conclusions</h4>These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation.
format	article
author	Tobias Eckle Kelley Brodsky Megan Bonney Thomas Packard Jun Han Christoph H Borchers Thomas J Mariani Douglas J Kominsky Michel Mittelbronn Holger K Eltzschig
author_facet	Tobias Eckle Kelley Brodsky Megan Bonney Thomas Packard Jun Han Christoph H Borchers Thomas J Mariani Douglas J Kominsky Michel Mittelbronn Holger K Eltzschig
author_sort	Tobias Eckle
title	HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
title_short	HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
title_full	HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
title_fullStr	HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
title_full_unstemmed	HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
title_sort	hif1a reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/59694fe8c1974a1ea3a346285a25ce33
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HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.

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