{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:58:01Z","timestamp":1754261881913,"version":"3.41.2"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The gasotransmitter H<jats:sub>2<\/jats:sub>S is involved in various physiological and pathophysiological processes. The aim of this study was to investigate the physiological functions of H<jats:sub>2<\/jats:sub>S in the lungs. In the model of mouse with genetic deficiency in a H<jats:sub>2<\/jats:sub>S natural synthesis enzyme cystathionine-<jats:italic>\u03b3<\/jats:italic>-lyase (CSE), we found that arterial oxygen saturation (SaO<jats:sub>2<\/jats:sub>) was decreased compared with wild type mice. Hypoxyprobe test showed that mild hypoxia occurred in the tissues of heart, lungs and kidneys in <jats:italic>Cse<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice. H<jats:sub>2<\/jats:sub>S donor GYY4137 treatment increased SaO<jats:sub>2<\/jats:sub> and ameliorated hypoxia state in cardiac and renal tissues. Further, we revealed that lung blood perfusion and airway responsiveness were not linked to reduced SaO<jats:sub>2<\/jats:sub> level. Lung injury was found in <jats:italic>Cse<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice as evidenced by alveolar wall thickening, diffuse interstitial edema and leukocyte infiltration in pulmonary tissues. IL-8, IL-1<jats:italic>\u03b2<\/jats:italic>, and TNF-<jats:italic>\u03b1<\/jats:italic> levels were markedly increased and oxidative stress levels were also significantly higher with increased levels of the pro-oxidative biomarker, MDA, decreased levels of the anti-oxidative biomarkers, T-AOC and GSH\/GSSG, and reduced superoxide dismutase (SOD) activity in lung tissues of <jats:italic>Cse<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice compared with those of wild type mice. GYY4137 treatment ameliorated lung injury and suppressed inflammatory state and oxidative stress in lung tissues of <jats:italic>Cse<\/jats:italic><jats:sup>-\/-<\/jats:sup> mice. A decrease in SaO<jats:sub>2<\/jats:sub> was found in normal mice under hypoxia. These mice displayed lung injury as evidenced by alveolar wall thickening, interstitial edema and leukocyte infiltration. Increased levels of inflammatory cytokines and oxidative stress were also found in lung tissues of the mice with hypoxia insult. GYY4137 treatment increased SaO<jats:sub>2<\/jats:sub> and ameliorated lung injury, inflammation and oxidative stress. Our data indicate that endogenous H<jats:sub>2<\/jats:sub>S is an important factor in maintaining normal SaO<jats:sub>2<\/jats:sub> by preventing oxidative stress and inflammation in the lungs.<\/jats:p>","DOI":"10.3389\/fphar.2021.677110","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T06:55:00Z","timestamp":1622444100000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Endogenous Hydrogen Sulfide Is an Important Factor in Maintaining Arterial Oxygen Saturation"],"prefix":"10.3389","volume":"12","author":[{"given":"Yan","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengshan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningning","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"421","DOI":"10.4149\/gpb_2018002","article-title":"H2S Attenuates Acute Lung Inflammation Induced by Administration of Lipopolysaccharide in Adult Male Rats","volume":"37","author":"Ali","year":"2018","journal-title":"Gen. Physicol. Biophys."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3402809","DOI":"10.1155\/2018\/3402809","article-title":"Hydrogen Sulfide Alleviates Acute Myocardial Ischemia Injury by Modulating Autophagy and Inflammation Response under Oxidative Stress","volume":"2018","author":"Bai","year":"2018","journal-title":"Oxid Med. Cel Longev"},{"key":"B3","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1161\/circulationaha.118.034757","article-title":"Cystathionine \u03b3 Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis","volume":"139","author":"Bibli","year":"2019","journal-title":"Circulation"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5698931","DOI":"10.1155\/2016\/5698931","article-title":"Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant Paradox?","volume":"2016","author":"Biswas","year":"2016","journal-title":"Oxid Med. Cel Longev"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2715","DOI":"10.2174\/1381612811319150006","article-title":"Hydrogen Sulfide Prevents Hyperoxia-Induced Lung Injury by Downregulating Reactive Oxygen Species Formation and Angiopoietin-2 Release","volume":"19","author":"Faller","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"B6","doi-asserted-by":"publisher","first-page":"14676","DOI":"10.1038\/s41598-018-33101-x","article-title":"Hydrogen Sulfide Limits Neutrophil Transmigration, Inflammation, and Oxidative Burst in Lipopolysaccharide-Induced Acute Lung Injury","volume":"8","author":"Faller","year":"2018","journal-title":"Sci. Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2872","DOI":"10.7150\/ijbs.38315","article-title":"Hydrogen Sulfide Treatment Alleviated Ventilator-Induced Lung Injury through Regulation of Autophagy and Endoplasmic Reticulum Stress","volume":"15","author":"Ge","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"105979","DOI":"10.1016\/j.intimp.2019.105979","article-title":"Hydrogen Sulfide Inhibits Cigarette Smoke-Induced Inflammation and Injury in Alveolar Epithelial Cells by Suppressing PHD2\/HIF-1\u03b1\/MAPK Signaling Pathway","volume":"81","author":"Guan","year":"2020","journal-title":"Int. Immunopharmacology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ejphar.2014.01.009","article-title":"Hydrogen Sulfide Protected Gastric Epithelial Cell from Ischemia\/reperfusion Injury by Keap1 S-Sulfhydration, MAPK Dependent Anti-apoptosis and NF-\u039ab Dependent Anti-inflammation Pathway","volume":"725","author":"Guo","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"878052","DOI":"10.1155\/2012\/878052","article-title":"Hydrogen Sulfide as an Endogenous Modulator in Mitochondria and Mitochondria Dysfunction","volume":"2012","author":"Guo","year":"2012","journal-title":"Oxid Med. Cel Longev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/molecules22081334","article-title":"H\u2082S-Mediated Protein S-Sulfhydration: A Prediction for its Formation and Regulation","volume":"22","author":"Ju","year":"2017","journal-title":"Molecules"},{"key":"B12","doi-asserted-by":"publisher","first-page":"C537","DOI":"10.1152\/ajpcell.00329.2016","article-title":"Vascular Biology of Hydrogen Sulfide","volume":"312","author":"Kanagy","year":"2017","journal-title":"Am. J. Physiology-Cell Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1007\/s00421-012-2584-5","article-title":"Treatment with Exogenous Hydrogen Sulfide Attenuates Hyperoxia-Induced Acute Lung Injury in Mice","volume":"113","author":"Li","year":"2013","journal-title":"Eur. J. Appl. Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"604944","DOI":"10.3389\/fimmu.2020.604944","article-title":"Adenosine at the Interphase of Hypoxia and Inflammation in Lung Injury","volume":"11","author":"Li","year":"2020","journal-title":"Front. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"6020","DOI":"10.1038\/ncomms7020","article-title":"Genetic Targeting of Sprouting Angiogenesis Using Apln-CreER","volume":"6","author":"Liu","year":"2015","journal-title":"Nat. Commun."},{"key":"B16","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.stem.2014.03.005","article-title":"Hydrogen Sulfide Maintains Mesenchymal Stem Cell Function and Bone Homeostasis via Regulation of Ca2+ Channel Sulfhydration","volume":"15","author":"Liu","year":"2014","journal-title":"Cell Stem Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"6325378","DOI":"10.1155\/2020\/6325378","article-title":"Hydrogen Sulfide Protects against Paraquat-Induced Acute Liver Injury in Rats by Regulating Oxidative Stress, Mitochondrial Function, and Inflammation","volume":"2020","author":"Liu","year":"2020","journal-title":"Oxid Med. Cel Longev"},{"key":"B18","doi-asserted-by":"publisher","first-page":"L710","DOI":"10.1152\/ajplung.00134.2015","article-title":"The H2S-Generating Enzymes Cystathionine \u03b2-synthase and Cystathionine \u03b3-lyase Play a Role in Vascular Development during normal Lung Alveolarization","volume":"309","author":"Madurga","year":"2015","journal-title":"Am. J. Physiology-Lung Cell Mol. Physiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1111\/bph.13861","article-title":"Hydrogen Sulfide Pretreatment Improves Mitochondrial Function in Myocardial Hypertrophy via a SIRT3-dependent Manner","volume":"175","author":"Meng","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.phrs.2016.08.023","article-title":"S- Sulfhydration of ATP Synthase by Hydrogen Sulfide Stimulates Mitochondrial Bioenergetics","volume":"113","author":"M\u00f3dis","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"13098","DOI":"10.1096\/fj.201901304r","article-title":"Hydrogen Sulfide Signaling in Mitochondria and Disease","volume":"33","author":"Murphy","year":"2019","journal-title":"FASEB J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/s0021-5198(19)39892-0","article-title":"Effect of Three Novel K+ Channel Openers, Cromakalim, Pinacidil and Nicorandil on Allergic Reaction and Experimental Asthma","volume":"56","author":"Nagai","year":"1991","journal-title":"Jpn. J. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.resp.2010.09.012","article-title":"Kidins220\/ARMS Contributes to Airway Inflammation and Hyper-Responsiveness in OVA-Sensitized Mice","volume":"175","author":"Ni","year":"2011","journal-title":"Respir. Physiol. Neurobiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"I264","DOI":"10.1161\/01.cir.0000032879.55215.f4","article-title":"In Vivo gene Transfection with Hepatocyte Growth Factor via the Pulmonary Artery Induces Angiogenesis in the Rat Lung","volume":"106","author":"Ono","year":"2002","journal-title":"Circulation"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3285074","DOI":"10.1155\/2016\/3285074","article-title":"Implications of Hydrogen Sulfide in Glucose Regulation: How H2S Can Alter Glucose Homeostasis through Metabolic Hormones","volume":"2016","author":"Pichette","year":"2016","journal-title":"Oxid Med. Cel Longev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"410","DOI":"10.3967\/bes2014.070","article-title":"H\u2082S Protecting against Lung Injury Following Limb Ischemia-Reperfusion by Alleviating Inflammation and Water Transport Abnormality in Rats","volume":"27","author":"Qi","year":"2014","journal-title":"Biomed. Environ. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.molcel.2011.10.021","article-title":"Hydrogen Sulfide-Linked Sulfhydration of NF-\u039ab Mediates its Antiapoptotic Actions","volume":"45","author":"Sen","year":"2012","journal-title":"Mol. Cel"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1161\/01.cir.0000158433.89103.85","article-title":"Amelioration of Pulmonary Emphysema by In Vivo Gene Transfection with Hepatocyte Growth Factor in Rats","volume":"111","author":"Shigemura","year":"2005","journal-title":"Circulation"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1568","DOI":"10.3389\/fphar.2019.01568","article-title":"Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link between Inflammation and Hydrogen Sulfide","volume":"10","author":"Sun","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"12086","DOI":"10.1038\/ncomms12086","article-title":"Sphingosine-1-phosphate Promotes Erythrocyte Glycolysis and Oxygen Release for Adaptation to High-Altitude Hypoxia","volume":"7","author":"Sun","year":"2016","journal-title":"Nat. Commun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3816","DOI":"10.3760\/cma.j.issn.0366-6999.2011.22.038","article-title":"Hydrogen Sulfide and Vascular Relaxation","volume":"124","author":"Sun","year":"2011","journal-title":"Chin. Med. J. (Engl)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"14971","DOI":"10.1038\/srep14971","article-title":"Metabolic Changes of H2S in Smokers and Patients of COPD Which Might Involve in Inflammation, Oxidative Stress and Steroid Sensitivity","volume":"5","author":"Sun","year":"2015","journal-title":"Sci. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.7150\/ijms.36516","article-title":"Potential for Therapeutic Use of Hydrogen Sulfide in Oxidative Stress-Induced Neurodegenerative Diseases","volume":"16","author":"Tabassum","year":"2019","journal-title":"Int. J. Med. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"46278","DOI":"10.1038\/srep46278","article-title":"New Method for Quantification of Gasotransmitter Hydrogen Sulfide in Biological Matrices by LC-MS\/MS","volume":"7","author":"Tan","year":"2017","journal-title":"Sci. Rep."},{"key":"B36","doi-asserted-by":"publisher","first-page":"3476","DOI":"10.3760\/cma.j.issn.0366-6999.2011.21.007","article-title":"Effect of Endogenous Hydrogen Sulfide on Oxidative Stress in Oleic Acid-Induced Acute Lung Injury in Rats","volume":"124","author":"Wang","year":"","journal-title":"Chin. Med. J. (Engl)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.1089\/ars.2013.5682","article-title":"CBS and CSE Are Critical for Maintenance of Mitochondrial Function and Glucocorticoid Production in Adrenal Cortex","volume":"21","author":"Wang","year":"2014","journal-title":"Antioxid. Redox Signaling"},{"key":"B38","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.mce.2018.02.011","article-title":"Endogenous H 2 S Resists Mitochondria-Mediated Apoptosis in the Adrenal Glands via ATP5A1 S-Sulfhydration in Male Mice","volume":"474","author":"Wang","year":"2018","journal-title":"Mol. Cell Endocrinol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"8877691","DOI":"10.1155\/2021\/8877691","article-title":"Hydrogen Sulfide Is a Regulator of Hemoglobin Oxygen-Carrying Capacity via Controlling 2,3-BPG Production in Erythrocytes","volume":"2021","author":"Wang","year":"2021","journal-title":"Oxid Med. Cel Longev"},{"key":"B40","doi-asserted-by":"publisher","first-page":"264","DOI":"10.7150\/ijbs.38143","article-title":"Hydrogen Sulfide Plays an Important Protective Role through Influencing Endoplasmic Reticulum Stress in Diseases","volume":"16","author":"Wang","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1159\/000320228","article-title":"Annexin 1-Derived Peptide Ac2-26 Inhibits Eosinophil Recruitment In Vivo via Decreasing Prostaglandin D2","volume":"154","author":"Wang","year":"","journal-title":"Int. Arch. Allergy Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1016\/j.cellsig.2013.07.010","article-title":"Dysregulation of Cystathionine \u03b3-lyase (CSE)\/hydrogen Sulfide Pathway Contributes to Ox-LDL-Induced Inflammation in Macrophage","volume":"25","author":"Wang","year":"2013","journal-title":"Cell Signal."},{"key":"B43","doi-asserted-by":"publisher","first-page":"758678","DOI":"10.1155\/2015\/758678","article-title":"Interaction of Hydrogen Sulfide with Oxygen Sensing under Hypoxia","volume":"2015","author":"Wu","year":"","journal-title":"Oxid Med. Cel Longev"},{"key":"B44","doi-asserted-by":"publisher","first-page":"186908","DOI":"10.1155\/2015\/186908","article-title":"Role of Hydrogen Sulfide in Ischemia-Reperfusion Injury","volume":"2015","author":"Wu","year":"","journal-title":"Oxid Med. Cel Longev"},{"key":"B45","doi-asserted-by":"publisher","first-page":"3171","DOI":"10.2337\/db16-0020","article-title":"Hydrogen Sulfide Induces Keap1 S-Sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation","volume":"65","author":"Xie","year":"2016","journal-title":"Diabetes"},{"key":"B46","doi-asserted-by":"publisher","first-page":"357824","DOI":"10.1155\/2015\/357824","article-title":"Hydrogen Sulfide Signaling in Oxidative Stress and Aging Development","volume":"2015","author":"Yang","year":"2015","journal-title":"Oxid Med. Cel Longev"},{"key":"B47","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1126\/science.1162667","article-title":"H2S as a Physiologic Vasorelaxant: Hypertension in Mice with Deletion of Cystathionine -Lyase","volume":"322","author":"Yang","year":"2008","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1089\/ars.2012.4645","article-title":"Hydrogen Sulfide Protects against Cellular Senescence via S-Sulfhydration of Keap1 and Activation of Nrf2","volume":"18","author":"Yang","year":"2013","journal-title":"Antioxid. Redox Signaling"},{"key":"B49","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.ejphar.2009.12.025","article-title":"Protective Effects of the Free Radical Scavenger Edaravone on Acute Pancreatitis-Associated Lung Injury","volume":"630","author":"Yang","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1016\/j.ajpath.2012.12.008","article-title":"The Inhibitory Role of Hydrogen Sulfide in Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma","volume":"182","author":"Zhang","year":"2013","journal-title":"Am. J. Pathol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1159\/000453210","article-title":"H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative\/Nitrative Stress and Inflammation","volume":"40","author":"Zhang","year":"2016","journal-title":"Cell Physiol Biochem"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1007\/s00018-009-0250-9","article-title":"Glucocorticoids Suppress Cystathionine Gamma-Lyase Expression and H2S Production in Lipopolysaccharide-Treated Macrophages","volume":"67","author":"Zhu","year":"2010","journal-title":"Cell. Mol. Life Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.677110\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T06:55:05Z","timestamp":1622444105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.677110\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,31]]},"references-count":51,"alternative-id":["10.3389\/fphar.2021.677110"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.677110","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2021,5,31]]},"article-number":"677110"}}