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

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 (H₂ S) has anti-inflammatory and vasodilatory effects with oxidative stress. There is little understanding of H₂ S signaling in developing airways. We hypothesized that the endogenous H₂ S system is detrimentally influenced by O₂ and conversely H₂ S 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 H₂ S machinery, and effects of exogenous H₂ S donors NaHS and GYY4137 in the context of moderate hyperoxia, with intracellular calcium regulation as a readout of contractility. Biochemical pathways for endogenous H₂ S generation and catabolism are present in fASM, and are differentially sensitive to O₂ toward overall reduction in H₂ S levels. H₂ S 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 H₂ S donors such as NaHS and GYY4137. These data provide novel information regarding the potential for H₂ S to act as a bronchodilator in developing airways in the context of oxygen exposure.