Bronchopulmonary Dysplasia and Pulmonary Hypertension. The Role of Smooth Muscle adh5
Autor: | Richard J. Martin, Ramadan B Sopi, Benjamin Gaston, Feifei Cui, Craig A. Hodges, Gail H. Deutsch, Rongli Zhang, Maureen O'Reilly, Anjum Jafri, Thomas M. Raffay, Peter M. MacFarlane, Laura Smith, Koby Bonilla-Fernandez |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Male medicine.medical_specialty Hypertension Pulmonary Clinical Biochemistry Myocytes Smooth Muscle behavioral disciplines and activities Muscle Smooth Vascular 03 medical and health sciences Mice 0302 clinical medicine Smooth muscle Internal medicine mental disorders medicine Animals Humans Child Molecular Biology Original Research Bronchopulmonary Dysplasia Mice Knockout business.industry Alcohol Dehydrogenase Infant Cell Biology respiratory system medicine.disease Pulmonary hypertension Airway hyperreactivity 030104 developmental biology 030228 respiratory system Bronchopulmonary dysplasia Child Preschool Cardiology Female business |
Zdroj: | Am J Respir Cell Mol Biol |
Popis: | Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5(−/−)) and conditional smooth muscle (smooth muscle/adh5(−/−)) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5(−/−) mice were protected from all three aspects of BPD, whereas smooth muscle/adh5(−/−) mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD. |
Databáze: | OpenAIRE |
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