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

  • Background: 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. Methods and Findings: 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. Conclusions: 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.
Metadaten
Author:Tobias Eckle, Kelley Brodsky, Megan Bonney, Thomas Packard, Jun Han, Christoph H. Borchers, Thomas J. Mariani, Douglas J. Kominsky, Michel Guy André MittelbronnORCiDGND, Holger K. Eltzschig
URN:urn:nbn:de:hebis:30:3-316843
DOI:https://doi.org/10.1371/journal.pbio.1001665
ISSN:1545-7885
ISSN:1544-9173
Parent Title (English):PLoS biology, volume 11, issue 9, e1001665 (2013)
Publisher:Public Library of Science
Place of publication:Lawrence, KS
Document Type:Article
Language:English
Date of Publication (online):2013/09/24
Date of first Publication:2013/09/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2013/09/25
Volume:11
Issue:(9): e1001665
Page Number:25
Note:
Copyright: © 2013 Eckle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
HeBIS-PPN:353288373
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell 3.0