Hydrogen sulfide, oxygen, and calcium regulation in developing human airway smooth muscle

Abstract

Preterm infants can develop airway hyperreactivity and impaired bronchodilation following supplemental O2 (hyperoxia) in early life, making it important to understand mechanisms of hyperoxia effects. Endogenous hydrogen sulfide (H2S) has anti‐inflammatory and vasodilatory effects with oxidative stress. There is little understanding of H2S signaling in developing airways. We hypothesized that the endogenous H2S system is detrimentally influenced by O2 and conversely H2S signaling pathways can be leveraged to attenuate deleterious effects of O2. Using human fetal airway smooth muscle (fASM) cells, we investigated baseline expression of endogenous H2S machinery, and effects of exogenous H2S donors NaHS and GYY4137 in the context of moderate hyperoxia, with intracellular calcium regulation as a readout of contractility. Biochemical pathways for endogenous H2S generation and catabolism are present in fASM, and are differentially sensitive to O2 toward overall reduction in H2S levels. H2S donors have downstream effects of reducing [Ca2+]i responses to bronchoconstrictor agonist via blunted plasma membrane Ca2+ influx: effects blocked by O2. However, such detrimental O2 effects are targetable by exogenous H2S donors such as NaHS and GYY4137. These data provide novel information regarding the potential for H2S to act as a bronchodilator in developing airways in the context of oxygen exposure.

Prednisone-hydrogen sulfide releasing hybrid shows improved therapeutic profile in asthma

“…Corticosteroid use in asthma in controlling inflammation is limited by the side effects and by insensitivity in some people ( Cazzola and Hanania, 2006 ; Bousquet et al, 2007 ; Kuna et al, 2007 ; Heffler et al, 2018 ). It is becoming increasingly clear that several airway diseases are associated with a state of H 2 S deficiency ( Chen et al, 2009a ; Chen et al, 2009b ; Bartman et al, 2020 ; Hughes et al, 2009 ). We have previously demonstrated the ability of H 2 S donors such as NaHS to modulate bronchial tone and reverse AHR ( Roviezzo et al, 2015 ).…”

Oxygen and mechanical stretch in the developing lung: risk factors for neonatal and pediatric lung disease

“…For example, studies using human fetal airway smooth muscle have shown dose-dependent effects with moderate oxygen increasing proliferation and higher levels (>60%) driving apoptosis ( 102 ). Furthermore, studies on human fetal airway smooth muscle have shown moderate hyperoxia increases airway hyperreactivity via intracellular calcium response to bronchoconstrictor agonists ( 102 , 142 , 143 ). In vivo studies using moderate hyperoxia in a neonatal mouse model have demonstrated structural and functional changes similar to those seen in asthma and reactive airway disease: increased airway hyperreactivity in response to methacholine challenge as well as increased ASM thickness and collagen deposition in the airway ( 100 , 132 ).…”