Abstract
Supplemental O2 (hyperoxia), necessary for maintenance of oxygenation in premature infants, contributes to neonatal and pediatric airway diseases including asthma. Airway smooth muscle (ASM) is a key resident cell type, responding to hyperoxia with increased contractility and remodeling [proliferation, extracellular matrix (ECM) production], making the mechanisms underlying hyperoxia effects on ASM significant. Recognizing that fetal lungs experience a higher extracellular Ca2+ ([Ca2+]o) environment, we previously reported that the calcium sensing receptor (CaSR) is expressed and functional in human fetal ASM (fASM). In this study, using fASM cells from 18 to 22 week human fetal lungs, we tested the hypothesis that CaSR contributes to hyperoxia effects on developing ASM. Moderate hyperoxia (50% O2) increased fASM CaSR expression. Fluorescence [Ca2+]i imaging showed hyperoxia increased [Ca2+]i responses to histamine that was more sensitive to altered [Ca2+]o, and promoted IP3 induced intracellular Ca2+ release and store-operated Ca2+ entry: effects blunted by the calcilytic NPS2143. Hyperoxia did not significantly increase mitochondrial calcium which was regulated by CaSR irrespective of oxygen levels. Separately, fASM cell proliferation and ECM deposition (collagens but not fibronectin) showed sensitivity to [Ca2+]o that was enhanced by hyperoxia, but blunted by NPS2143. Effects of hyperoxia involved p42/44 ERK via CaSR and HIF1α. These results demonstrate functional CaSR in developing ASM that contributes to hyperoxia-induced contractility and remodeling that may be relevant to perinatal airway disease.
Highlights
Supplemental O2 even at moderate levels (≤ 50% O2) is an necessary intervention in the context of premature birth to maintain oxygenation and ensure survival
We previously showed that calcium sensing receptor (CaSR) was localized to smooth muscle layers of airways in human fetuses
We previously showed that [Ca2+]i in fASM cells increases in response to agonists such as ACh and histamine (Hartman et al, 2012; Roesler et al, 2019)
Summary
Supplemental O2 (hyperoxia) even at moderate levels (≤ 50% O2) is an necessary intervention in the context of premature birth to maintain oxygenation and ensure survival. CaSR, Oxygen, and Developing Airway deposition (Hartman et al, 2012; Vogel et al, 2017) Such effects are noted in newborn mouse models of moderate hyperoxia exposure that show persistent increases in bronchial wall diameter and enhanced responses to methacholine challenge (Wang et al, 2014; Onugha et al, 2015). The mechanisms of hyperoxia effects in fASM are not well-known In this regard, an important aspect of fetal development is that the extracellular environment that regulates airway growth shows higher extracellular Ca2+ ([Ca2+]o) level of ∼1.7 mM compared to adult (∼1.2 mM) (Kovacs and Kronenberg, 1997; Riccardi et al, 2013). In the present study, we explored the hypothesis that the CaSR contributes to hyperoxia effects on fASM in the context of enhanced contractility and remodeling
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