Hydrogen Sulfide in Neonatal Airway Disease

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ABSTRACT Moderate (<60%) O2 (hyperoxia) in premature infants promotes bronchial airway hyperresponsiveness (AHR) via effects on airway smooth muscle (ASM), a cell type that also contributes to impaired bronchodilation, and remodeling (proliferation, altered extracellular matrix (ECM)). Thus understanding mechanisms by which O2 affects bronchial airways is critical for therapeutic strategies in a vulnerable population. We propose a protective role for hydrogen sulfide (H2S) in developing airways that can be leveraged in prematurity, thus providing clinical significance to our proposal. We hypothesize that the protective endogenous H2S system is detrimentally influenced by O2, but that exogenous H2S donors can be used to counteract detrimental effects of O2 on contractility and remodeling. Little is known regarding regulation of endogenous H2S in developing bronchial airways, and mechanisms by which moderate O2 reduces H2S. Conversely, the mechanisms by which H2S impacts on developing airways to alleviate O2 effects are unknown. We propose 3 Aims using human fetal lung and in vivo neonatal mouse models of O2 to explore these concepts. Aim 1: In developing human ASM, determine influence of O2 on endogenous H2S; Aim 2: In developing human ASM, determine mechanisms by which H2S alleviates O2-enhanced airway contractility and remodeling; Aim 3: In a newborn mouse model of hyperoxia, determine effects of H2S on airway contractility and remodeling. In Aim 1, we will use 18-22 wk gestation human fetal ASM (fASM) to examine mechanisms by which O2 decreases H2S, focusing on ROS, mitochondria, and alterations in the methionine-transsulfuration balance that can drive changes in the H2S synthesis enzyme CBS. Aim 2 explores downstream effects of H2S (via donors NaHS and GYY4137, and enhancement of endogenous H2S) in the context of contractility and remodeling following 40% O2. Here, the focus is on three key mechanisms: suppression of HIF1α, activation of Nrf2, and enhancement of cAMP. In Aim 3, in vitro studies are integrated using a newborn mouse model of hyperoxia where early exposure to moderate oxygen levels results in sustained AHR and remodeling. The efficacy of H2S donors in alleviating AHR and remodeling is assessed. Clinical significance lies in establishing the importance of H2S in O2 effects on developing airway towards future therapeutic targeting for neonatal asthma.