title: Hydrogen Sulfide Prevents Formation of Reactive Oxygen Species through PI3K/Akt Signaling and Limits Ventilator-Induced Lung Injury.
abstract: The development of ventilator-induced lung injury (VILI) is still a major problem in mechanically ventilated patients. Low dose inhalation of hydrogen sulfide (H2S) during mechanical ventilation has been proven to prevent lung damage by limiting inflammatory responses in rodent models. However, the capacity of H2S to affect oxidative processes in VILI and its underlying molecular signaling pathways remains elusive. In the present study we show that ventilation with moderate tidal volumes of 12 ml/kg for 6 h led to an excessive formation of reactive oxygen species (ROS) in mice lungs which was prevented by supplemental inhalation of 80 parts per million of H2S. In addition, phosphorylation of the signaling protein Akt was induced by H2S. In contrast, inhibition of Akt by LY294002 during ventilation reestablished lung damage, neutrophil influx, and proinflammatory cytokine release despite the presence of H2S. Moreover, the ability of H2S to induce the antioxidant glutathione and to prevent ROS production was reversed in the presence of the Akt inhibitor. Here, we provide the first evidence that H2S-mediated Akt activation is a key step in protection against VILI, suggesting that Akt signaling limits not only inflammatory but also detrimental oxidative processes that promote the development of lung injury.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Sashko Georgiev
authors.initials: SG
authors.lastname: Spassov
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Rosa
authors.initials: R
authors.lastname: Donus
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Paul Mikael
authors.initials: PM
authors.lastname: Ihle
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Engelstaedter
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoetzel
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Simone
authors.identifier: 0000-0001-5345-8523
authors.initials: S
authors.lastname: Faller
mesh_terms: D000818:Animals; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D006862:Hydrogen Sulfide / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D006862:Hydrogen Sulfide