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Bronchopulmonary Dysplasia and Pulmonary Hypertension: The Role of Smooth Muscle adh5 .

Research paper by Thomas M TM Raffay, Koby K Bonilla-Fernandez, Anjum A Jafri, Ramadan B RB Sopi, Laura A LA Smith, Feifei F Cui, Maureen M O'Reilly, Rongli R Zhang, Craig A CA Hodges, Peter M PM MacFarlane, Gail G Deutsch, Richard J RJ Martin, Benjamin B Gaston

Indexed on: 31 Mar '21Published on: 30 Mar '21Published in: American journal of respiratory cell and molecular biology



Abstract

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 S-nitrosoglutathione (GSNO). We have shown the GSNO catabolic enzyme encoded by adh5, GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigate the distribution of GSNO reductase expression in human BPD and create an animal model which 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 (SM/adh5-/-) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared to 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 SM/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.