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Supplemental O 2 remains a necessary intervention for many premature infants (<34 wk gestation). Even moderate hyperoxia (<60% O 2 ) poses a risk for subsequent airway disease, thereby predisposing premature infants to pediatric asthma involving chronic inflammation, airway hyperresponsiveness (AHR), airway remodeling, and airflow obstruction. Moderate hyperoxia promotes AHR via effects on airway smooth muscle (ASM), a cell type that also contributes to impaired bronchodilation and remodeling (proliferation, altered extracellular matrix). Understanding mechanisms by which O 2 initiates long-term airway changes in prematurity is critical for therapeutic advancements for wheezing disorders and asthma in babies and children. Immature or dysfunctional antioxidant systems in the underdeveloped lungs of premature infants thereby heightens susceptibility to oxidative stress from O 2 . The novel gasotransmitter hydrogen sulfide (H 2 S) is involved in antioxidant defense and has vasodilatory effects with oxidative stress. We previously showed that exogenous H 2 S exhibits bronchodilatory effects in human developing airway in the context of hyperoxia exposure. Here, we proposed that exogenous H 2 S would attenuate effects of O 2 on airway contractility, thickness, and remodeling in mice exposed to hyperoxia during the neonatal period. Using functional [flexiVent; precision-cut lung slices (PCLS)] and structural (histology; immunofluorescence) analyses, we show that H 2 S donors mitigate the effects of O 2 on developing airway structure and function, with moderate O 2 and H 2 S effects on developing mouse airways showing a sex difference. Our study demonstrates the potential applicability of low-dose H 2 S toward alleviating the detrimental effects of hyperoxia on the premature lung. NEW & NOTEWORTHY Chronic airway disease is a short- and long-term consequence of premature birth. Understanding effects of O 2 exposure during the perinatal period is key to identify targetable mechanisms that initiate and sustain adverse airway changes. Our findings show a beneficial effect of exogenous H 2 S on developing mouse airway structure and function with notable sex differences. H 2 S donors alleviate effects of O 2 on airway hyperreactivity, contractility, airway smooth muscle thickness, and extracellular matrix deposition.

The use of respiratory support strategies such as continuous positive airway pressure in premature infants can substantially stretch highly compliant perinatal airways, leading to airway hyperreactivity and remodeling in the long term. The mechanisms by which stretch detrimentally affects the airway are unknown. Airway smooth muscle cells play a critical role in contractility and remodeling. Using 18-22-wk gestation human fetal airway smooth muscle (fASM) as an in vitro model, we tested the hypothesis that mechanosensitive Piezo (PZ) channels contribute to stretch effects. We found that PZ1 and PZ2 channels are expressed in the smooth muscle of developing airways and that their expression is influenced by stretch. PZ activation via agonist Yoda1 or stretch results in significant [Ca 2+ ] i responses as well as increased extracellular matrix production. These data suggest that functional PZ channels may play a role in detrimental stretch-induced airway changes in the context of prematurity. NEW & NOTEWORTHY Piezo channels were first described just over a decade ago and their function in the lung is largely unknown. We found that piezo channels are present and functional in the developing airway and contribute to intracellular calcium responses and extracellular matrix remodeling in the setting of stretch. This may improve our understanding of the mechanisms behind development of chronic airway diseases, such as asthma, in former preterm infants exposed to respiratory support, such as continuous positive airway pressure (CPAP).

The detrimental effects of tobacco exposure on children's health are well known. Nonetheless, the prevalence of secondhand or direct cigarette smoke exposure (CSE) in the pediatric population has not significantly decreased over time. On the contrary, the rapid incline in use of e-cigarettes among adolescents has evoked public health concerns since increasing cases of vaping-induced acute lung injury have highlighted the potential harm of these new "smoking" devices. Two pediatric populations are especially vulnerable to the detrimental effects of cigarette smoke. The first group is former premature infants whose risk is elevated both due to their prematurity as well as other risk factors such as oxygen and mechanical ventilation to which they are disproportionately exposed. The second group is children and adolescents with chronic respiratory diseases, in particular asthma and other wheezing disorders. Coronavirus disease 2019 (COVID-19) is a spectrum of diseases caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread worldwide over the last year. Here, respiratory symptoms ranging from mild to acute respiratory distress syndrome (ARDS) are at the forefront of COVID-19 cases among adults, and cigarette smoking is associated with worse outcomes in this population, and cigarette smoking is associated with worse outcomes in this population. Interestingly, SARS-CoV-2 infection affects children differently in regard to infection susceptibility, disease manifestations, and complications. Although children carry and transmit the virus, the likelihood of symptomatic infection is low, and the rates of hospitalization and death are even lower when compared to the adult population. However, multisystem inflammatory syndrome is recognized as a serious consequence of SARS-CoV-2 infection in the pediatric population. In addition, recent data demonstrate specific clinical patterns in children infected with SARS-CoV-2 who develop multisystem inflammatory syndrome vs. severe COVID-19. In this review, we highlight the pulmonary effects of CSE in vulnerable pediatric populations in the context of the ongoing SARS-CoV-2 pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schiliro, Vogel, Paolini and Pabelick.)

Supplemental O 2 (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 Ca 2+ ([Ca 2+ ] 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% O 2 ) increased fASM CaSR expression. Fluorescence [Ca 2+ ] i imaging showed hyperoxia increased [Ca 2+ ] i responses to histamine that was more sensitive to altered [Ca 2+ ] o , and promoted IP 3 induced intracellular Ca 2+ release and store-operated Ca 2+ 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 [Ca 2+ ] 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Roesler, Ravix, Bartman, Patel, Schiliro, Roos, Nesbitt, Pabelick, Martin, MacFarlane and Prakash.)

Introduction: Airway dysfunction leading to chronic lung disease is a common consequence of premature birth and mechanisms responsible for early and progressive airway remodeling are not completely understood. Current therapeutic options are only partially effective in reducing the burden of neonatal airway disease and premature decline of lung function. Gasotransmitter hydrogen sulfide (H 2 S) has been recently recognized for its therapeutic potential in lung diseases., Areas Covered: Contradictory to its well-known toxicity at high concentrations, H 2 S has been characterized to have anti-inflammatory, antioxidant, and antiapoptotic properties at physiological concentrations. In the respiratory system, endogenous H 2 S production participates in late lung development and exogenous H 2 S administration has a protective role in a variety of diseases such as acute lung injury and chronic pulmonary hypertension and fibrosis. Literature searches performed using NCBI PubMed without publication date limitations were used to construct this review, which highlights the dichotomous role of H 2 S in the lung, and explores its promising beneficial effects in lung diseases., Expert Opinion: The emerging role of H 2 S in pathways involved in chronic lung disease of prematurity along with its recent use in animal models of BPD highlight H 2 S as a potential novel candidate in protecting lung function following preterm birth.

Preterm infants can develop airway hyperreactivity and impaired bronchodilation following supplemental O 2 (hyperoxia) in early life, making it important to understand mechanisms of hyperoxia effects. Endogenous hydrogen sulfide (H 2 S) has anti-inflammatory and vasodilatory effects with oxidative stress. There is little understanding of H 2 S signaling in developing airways. We hypothesized that the endogenous H 2 S system is detrimentally influenced by O 2 and conversely H 2 S signaling pathways can be leveraged to attenuate deleterious effects of O 2 . Using human fetal airway smooth muscle (fASM) cells, we investigated baseline expression of endogenous H 2 S machinery, and effects of exogenous H 2 S donors NaHS and GYY4137 in the context of moderate hyperoxia, with intracellular calcium regulation as a readout of contractility. Biochemical pathways for endogenous H 2 S generation and catabolism are present in fASM, and are differentially sensitive to O 2 toward overall reduction in H 2 S levels. H 2 S donors have downstream effects of reducing [Ca 2+ ] i responses to bronchoconstrictor agonist via blunted plasma membrane Ca 2+ influx: effects blocked by O 2 . However, such detrimental O 2 effects are targetable by exogenous H 2 S donors such as NaHS and GYY4137. These data provide novel information regarding the potential for H 2 S to act as a bronchodilator in developing airways in the context of oxygen exposure., (© 2020 Federation of American Societies for Experimental Biology.)

There is marked sexual dimorphism in the current coronavirus disease 2019 (COVID-19) pandemic. Here we report that estrogen can regulate the expression of angiotensin-converting enzyme 2 (ACE2), a key component for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry, in differentiated airway epithelial cells. Further studies are required to elucidate the mechanisms by which sex steroids regulate SARS-CoV-2 infectivity.