title: The H2S-generating enzymes cystathionine β-synthase and cystathionine γ-lyase play a role in vascular development during normal lung alveolarization.
abstract: The gasotransmitter hydrogen sulfide (H2S) is emerging as a mediator of lung physiology and disease. Recent studies revealed that H2S administration limited perturbations to lung structure in experimental animal models of bronchopulmonary dysplasia (BPD), partially restoring alveolarization, limiting pulmonary hypertension, limiting inflammation, and promoting epithelial repair. No studies have addressed roles for endogenous H2S in lung development. H2S is endogenously generated by cystathionine β-synthase (Cbs) and cystathionine γ-lyase (Cth). We demonstrate here that the expression of Cbs and Cth in mouse lungs is dynamically regulated during lung alveolarization and that alveolarization is blunted in Cbs(-/-) and Cth(-/-) mouse pups, where a 50% reduction in the total number of alveoli was observed, without any impact on septal thickness. Laser-capture microdissection and immunofluorescence staining indicated that Cbs and Cth were expressed in the airway epithelium and lung vessels. Loss of Cbs and Cth led to a 100-500% increase in the muscularization of small- and medium-sized lung vessels, which was accompanied by increased vessel wall thickness, and an apparent decrease in lung vascular supply. Ablation of Cbs expression using small interfering RNA or pharmacological inhibition of Cth using propargylglycine in lung endothelial cells limited angiogenic capacity, causing a 30-40% decrease in tube length and a 50% decrease in number of tubes formed. In contrast, exogenous administration of H2S with GYY4137 promoted endothelial tube formation. These data confirm a key role for the H2S-generating enzymes Cbs and Cth in pulmonary vascular development and homeostasis and in lung alveolarization.
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Alicia
authors.initials: A
authors.lastname: Madurga
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Anita
authors.initials: A
authors.lastname: Golec
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Pozarska
authors.affiliation: Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan;
authors.forename: Isao
authors.initials: I
authors.lastname: Ishii
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Ivana
authors.initials: I
authors.lastname: Mižíková
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Claudio
authors.initials: C
authors.lastname: Nardiello
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany;
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany;
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.affiliation: Department of Pulmonology, Asklepios Lung Centre, Munich-Gauting, Germany; and.
authors.forename: Frank
authors.initials: F
authors.lastname: Reichenberger
authors.affiliation: Division of Experimental Pneumology, Priority Area Asthma and Allergy, Airway Research Center North, German Center for Lung Research, Borstel, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Fehrenbach
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; rory.morty@mpi-bn.mpg.de.
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000096:biosynthesis* / Q000235:genetics; D003542:Cystathionine gamma-Lyase / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000196:embryology / Q000201:enzymology; D020545:Respiratory Mucosa / Q000098:blood supply / Q000196:embryology / Q000201:enzymology
chemical_list: D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: H2S; alveolarization; gasotransmitter; hydrogen sulfide; lung development