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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents



ID: 723960.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
The H2S-generating enzymes cystathionine beta-synthase and cystathionine gamma-lyase play a role in vascular development during normal lung alveolarization
Authors:Madurga, A.; Golec, A.; Pozarska, A.; Ishii, I.; Mizikova, I.; Nardiello, C.; Vadasz, I.; Herold, S.; Mayer, K.; Reichenberger, F.; Fehrenbach, H.; Seeger, W.; Morty, R. E.
Date of Publication (YYYY-MM-DD):2015-10-01
Title of Journal:Am J Physiol Lung Cell Mol Physiol
Volume:309
Issue / Number:7
Start Page:L710
End Page:24
Audience:Not Specified
Abstract / Description: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 beta-synthase (Cbs) and cystathionine gamma-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.
Free Keywords:Animals; Cystathionine beta-Synthase/*biosynthesis/genetics; Cystathionine gamma-Lyase/*biosynthesis/genetics; Gene Expression Regulation, Developmental/*physiology; Gene Expression Regulation, Enzymologic/*physiology; Hydrogen Sulfide/*metabolism; Mice; Mice, Knockout; *Pulmonary Alveoli/blood supply/embryology/enzymology; *Respiratory Mucosa/blood supply/embryology/enzymology; H2s; alveolarization; gasotransmitter; hydrogen sulfide; lung development
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; Department of Pulmonology, Asklepios Lung Centre, Munich-Gauting, Germany; and. Division of Experimental Pneumology, Priority Area Asthma and Allergy, Airway Research Center North, German Center for Lung Research, Borstel, Germany. 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.
Identifiers:ISSN:1522-1504 (Electronic) 1040-0605 (Linking) %R 10.1152/ajplung.00134.2015
URL:http://www.ncbi.nlm.nih.gov/pubmed/26232299
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