Browsing by Subject "Airway hyperreactivity"

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    Bronchopulmonary Dysplasia and Pulmonary Hypertension. The Role of Smooth Muscle adh5
    (American Thoracic Society, 2021-07) Raffay, Thomas M.; Bonilla-Fernandez, Koby; Jafri, Anjum; Sopi, Ramadan B.; Smith, Laura A.; Cui, Feifei; O’Reilly, Maureen; Zhang, Rongli; Hodges, Craig A.; MacFarlane, Peter M.; Deutsch, Gail; Martin, Richard J.; Gaston, Benjamin; Pediatrics, School of Medicine
    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.
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    S-nitrosylation is required for β2AR desensitization and experimental asthma
    (Elsevier, 2022) Fonseca, Fabio V.; Raffay, Thomas M.; Xiao, Kunhong; McLaughlin, Precious J.; Qian, Zhaoxia; Grimmett, Zachary W.; Adachi, Naoko; Wang, Benlian; Hausladen, Alfred; Cobb, Brian A.; Zhang, Rongli; Hess, Douglas T.; Gaston, Benjamin; Lambert, Nevin A.; Reynolds, James D.; Premont, Richard T.; Stamler, Jonathan S.; Pediatrics, School of Medicine
    The β2-adrenergic receptor (β2AR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of β-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation, the β2AR is modified by S-nitrosylation, which is essential for both classic desensitization by PKA as well as desensitization of NO-based signaling that mediates bronchorelaxation. Strikingly, S-nitrosylation alone can drive β2AR internalization in the absence of traditional agonist. Mutant β2AR refractory to S-nitrosylation (Cys265Ser) exhibits reduced desensitization and internalization, thereby amplifying NO-based signaling, and mice with Cys265Ser mutation are resistant to bronchoconstriction, inflammation, and the development of asthma. S-nitrosylation is thus a central mechanism in β2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain.