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Exogenous hydrogen sulfide (H2S) protects alveolar growth in experimental O2-induced neonatal lung injury.

AbstractBACKGROUND:
Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, remains a major health problem. BPD is characterized by impaired alveolar development and complicated by pulmonary hypertension (PHT). Currently there is no specific treatment for BPD. Hydrogen sulfide (H2S), carbon monoxide and nitric oxide (NO), belong to a class of endogenously synthesized gaseous molecules referred to as gasotransmitters. While inhaled NO is already used for the treatment of neonatal PHT and currently tested for the prevention of BPD, H2S has until recently been regarded exclusively as a toxic gas. Recent evidence suggests that endogenous H2S exerts beneficial biological effects, including cytoprotection and vasodilatation. We hypothesized that H2S preserves normal alveolar development and prevents PHT in experimental BPD.
METHODS:
We took advantage of a recently described slow-releasing H2S donor, GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) to study its lung protective potential in vitro and in vivo.
RESULTS:
In vitro, GYY4137 promoted capillary-like network formation, viability and reduced reactive oxygen species in hyperoxia-exposed human pulmonary artery endothelial cells. GYY4137 also protected mitochondrial function in alveolar epithelial cells. In vivo, GYY4137 preserved and restored normal alveolar growth in rat pups exposed from birth for 2 weeks to hyperoxia. GYY4137 also attenuated PHT as determined by improved pulmonary arterial acceleration time on echo-Doppler, pulmonary artery remodeling and right ventricular hypertrophy. GYY4137 also prevented pulmonary artery smooth muscle cell proliferation.
CONCLUSIONS:
H2S protects from impaired alveolar growth and PHT in experimental O2-induced lung injury. H2S warrants further investigation as a new therapeutic target for alveolar damage and PHT.
AuthorsArul Vadivel, Rajesh S Alphonse, Lavinia Ionescu, Desiree S Machado, Megan O'Reilly, Farah Eaton, Al Haromy, Evangelos D Michelakis, Bernard Thébaud
JournalPloS one (PLoS One) Vol. 9 Issue 3 Pg. e90965 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID24603989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • GYY 4137
  • Morpholines
  • Organothiophosphorus Compounds
  • Prodrugs
  • Protective Agents
  • Reactive Oxygen Species
  • Oxygen
  • Hydrogen Sulfide
Topics
  • Animals
  • Animals, Newborn
  • Bronchopulmonary Dysplasia (drug therapy, metabolism, pathology)
  • Disease Models, Animal
  • Endothelial Cells (drug effects, metabolism, pathology)
  • Humans
  • Hydrogen Sulfide (pharmacology)
  • Hyperoxia (chemically induced, drug therapy, metabolism, pathology)
  • Infant, Newborn
  • Lung (drug effects, metabolism, pathology)
  • Lung Injury (chemically induced, metabolism, pathology, prevention & control)
  • Mitochondria (drug effects, metabolism, pathology)
  • Morpholines (chemistry, pharmacology)
  • Organothiophosphorus Compounds (chemistry, pharmacology)
  • Oxygen (adverse effects)
  • Prodrugs (chemistry, pharmacology)
  • Protective Agents (pharmacology)
  • Pulmonary Alveoli (drug effects, metabolism, pathology)
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species (antagonists & inhibitors, metabolism)

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